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Review of the Parkinson’s Disease Drug Apomorphine (APOKYN)

Worst Pills, Best Pills Newsletter article January, 2019

Parkinson's disease (PD) is one the most common neurodegenerative disorders, second only to Alzheimer's disease.[1] It is associated with damage to the dopamine-producing nerve cells in one part of the brain that controls movement.[2] This is believed to cause the typical disabling motor symptoms of the disease: disturbances in swallowing and talking, balance, muscle strength, posture and walking; rigid muscles; and tremor (shaking). PD also can be associated with nonmotor symptoms,...

Parkinson's disease (PD) is one the most common neurodegenerative disorders, second only to Alzheimer's disease.[1] It is associated with damage to the dopamine-producing nerve cells in one part of the brain that controls movement.[2] This is believed to cause the typical disabling motor symptoms of the disease: disturbances in swallowing and talking, balance, muscle strength, posture and walking; rigid muscles; and tremor (shaking). PD also can be associated with nonmotor symptoms, including depression and cognitive impairment,[3] especially at its advanced stages.

Currently, there is no cure for PD. However, there are medications that can alleviate symptoms and improve quality of life for affected patients for many years. Apomorphine (APOKYN) is one such drug that was approved by the Food and Drug Administration (FDA) in 2004 to treat symptoms of immobility episodes in patients with advanced PD.

PD patients who take apomorphine or their caregivers need to work closely with the prescribing doctor to learn how and when to use this injectable drug and how to manage its numerous bothersome, and sometimes serious, adverse effects.

Limited role: Acute episodes of advanced PD

Similar to other dopamine agonists, apomorphine acts as a substitute for dopamine in the brain. It improves muscle control and reduces stiffness, allowing more normal movements of the body in PD patients.

However, apomorphine is approved for intermittent use in patients with advanced PD only to relieve the acute motor symptoms that occur in two cases: (1) "off" episodes (immobility due to muscle stiffness and loss of muscle control) and (2) unpredictable "on/off" episodes, the switch between mobility and immobility periods.[4] Three small clinical trials showed that apomorphine is more effective than placebo in the treatment of these disabling episodes in patients with advanced PD.[5]

Notably, these "off" and unpredictable "on/off" episodes occur when the benefit of the standard oral PD drug (levodopa-carbidopa [RYTARY, SINEMET]) to treat motor symptoms of the disease wears off.[6] Therefore, apomorphine is considered a rescue therapy[7] rather than maintenance (long-term) therapy. It has been studied and is used as a temporary add-on therapy to maintenance PD drugs.

Apomorphine management[8],[9]

Similar to insulin in diabetic individuals, apomorphine is injected under the skin using a thin needle. However, apomorphine is taken on an as-needed basis. Importantly, the drug should not be injected into a vein because doing so can cause a blood clot, which could lead to a life-threatening pulmonary embolism (a clot in the lung).

To determine the appropriate dose of apomorphine, patients are asked by their prescribing doctors to stop taking all of their PD drugs briefly in order to trigger an immobility episode.

The drug starts working quickly (as early as 10 minutes after injection), with most people feeling relief from the "off" period within 20 minutes after injection. Apomorphine's effects last for 60 to 90 minutes, so multiple intermittent injections usually are needed. Because of its short-term action, patients should continue their standard PD drugs when they take apomorphine once the appropriate dose is determined.

Experimental pump devices that administer apomorphine through continuous infusion under the skin are available. However, these pumps have not been approved by the FDA.

Drug-related adverse effects[10]

In clinical trials, nearly nine in 10 subjects given apomorphine experienced at least one adverse effect related to this drug.[11] Severe nausea and vomiting were the most common adverse effects. Even with the use of trimethobenzamide (TIGAN), a standard anti-nausea drug used concomitantly with apomorphine, 31 percent of apomorphine subjects experienced nausea and 11 percent experienced vomiting in these trials.

Apomorphine causes orthostatic hypotension (a drop in blood pressure when moving from a lying or seated position to a standing position, causing lightheadedness and possibly fainting), especially during dose increases and when the drug is taken with alcohol and blood-pressure-lowering drugs. Furthermore, falls were reported in 30 percent of apomorphine subjects in clinical trials, and 5 percent of these falls were considered serious.

Apomorphine may cause or worsen dyskinesia (abnormal, involuntary movements such as fidgeting, wriggling, head bobbing or body swaying). Such movements were reported in 24 percent of apomorphine subjects in clinical trials.

Drowsiness occurred in 35 percent of apomorphine subjects and in no subjects receiving a placebo in clinical trials. There also have been reports of patients using apomorphine who fell asleep suddenly without prior warning of sleepiness while they were performing their activities of daily living.

Hallucinations (seeing or hearing things that are not real) were reported in 14 percent of apomorphine subjects in clinical studies. In one placebo-controlled trial, hallucinations occurred in 10 percent of apomorphine subjects and in no placebo subjects. Other manifestations of psychotic-like behavior (including aggressiveness, agitation, delusions and excessive suspicion) have been reported with use of this drug.

Infrequent but serious adverse effects associated with apomorphine include coronary events (chest pain, heart attack or cardiac arrest), sudden death and priapism (prolonged painful erection in men).

The drug also can cause swelling of the arms and legs and injectionsite reactions, including bruising and itching.

Impulse control and compulsive behavior

Similar to five other dopamine agonists, apomorphine stimulates certain brain neurons considered to be involved in helping people avoid risks and seek rewards.[12] Stimulating these neurons sends part of the brain into overdrive, potentially leading some patients to engage in uncontrollable impulsive behaviors. These behaviors include compulsive gambling and shopping, hypersexuality and, more rarely, binge eating and "punding," which is a compulsive fascination with performing repetitive mechanical tasks, such as sorting or counting objects.[13] In severe cases, impulse-control problems and compulsive behaviors can have devastating, life-altering effects such as divorces, financial ruin, criminal charges and suicide attempts.

Some estimates suggest that as many as one-quarter of patients taking a dopamine agonist, including apomorphine, may have experienced a compulsive disorder.[14] In some cases, these impulse disorders reportedly stopped when the dose of the drug was reduced or when it was discontinued.[15] Importantly, these abnormal behaviors do not appear to be increased by the standard oral dopamine agonist PD drug, levodopa-carbidopa.

What You Can Do

If you are taking apomorphine or any other dopamine agonist, or if you are a caregiver of someone who is taking such drugs, keep regular appointments with the treating doctor to monitor the drug effect and to evaluate its adverse effects. Be careful when standing up while using apomorphine.

Importantly, watch for signs of new or increased impulse-control problems and compulsive behaviors (see text box, above) or psychotic-like behavior when taking these drugs. Promptly talk to the prescribing doctor if any of these adverse effects develop and ask him or her to consider reducing the dose, stopping the medication or replacing it with an alternative drug that does not cause these adverse effects. Do not stop taking apomorphine, or any PD drug, without speaking to your doctor first because doing so can cause problems.


References

[1] National Institute of Environmental Health Sciences. Neurodegenerative diseases. https://www.niehs.nih.gov/research/supported/health/neurodegenerative/index.cfm. Accessed October 29, 2018.

[2] Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683.

[3] Ibid.

[4] US WorldMeds. Label: apomorphine (APOKYN). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021264s014lbl.pdf. Accessed October 29, 2018.

[5] Ibid.

[6] Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: A review. JAMA. 2014;311(16):1670-1683.

[7] Jenner P, Katzenschlager R. Apomorphine - pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord. 2016;33(Dec):S13-S21.

[8] US WorldMeds. Label: apomorphine (APOKYN). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021264s014lbl.pdf. Accessed October 29, 2018.

[9] US WorldMeds. APOKYN: Frequently asked questions. 2016. https://www.apokyn.com/sites/all/themes/apokyn/content/resources/APO_FAQ_Booklet.pdf. Accessed October 29, 2018.

[10] US WorldMeds. Label: apomorphine (APOKYN). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021264s014lbl.pdf. Accessed October 29, 2018.

[11] Haq IU, Lewitt PA, Fernandez HH. Apomorphine therapy in Parkinson's disease: a review. Expert Opin Pharmacother. 2007;8(16):2799-2809.

[12] Gambling, hypersexuality and compulsive shopping: Drugs that make you. Worst Pills, Best Pills News. January, 2015. /newsletters/view/937. Accessed October 29, 2018.

[13] Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med. 2014;174(12):1930-1933.

[14] Ibid.

[15] US WorldMeds. Label: apomorphine (APOKYN). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021264s014lbl.pdf. Accessed October 29, 2018.

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