Brand Name

Labeled Uses: Treatment of hypomobility, “off” episodes associated with Parkinson’s disease.^1,2,3,4

Mechanism of Action: The exact mechanism of action for the treatment of Parkinson’s disease is unknown; however, it is thought that it works by stimulating dopamine type two (D₂) receptors in the caudate-putamen in the brain.^1,2,3,4

Pharmacokinetics^1,3,4
Tmax (min)	10- 60
Vd (L)	123- 404
T_1/2(min)	30- 60
Cl (L/hr)	125- 401
Protein Binding	N/A
F	About=100%

Metabolism: The exact rout of metabolism is not known; however potential routes of metabolism include sulfation, N- demethylation, glucuronidation and oxidation.^1,3,4 Major metabolites have not been identified yet.^1,3,4

Elimination: Apomorphine is 93% excreted by the kidneys, and 16% excreted in the feces.³

Citation: Levy R., et al. Effects of Apomorphine on Subthalamic Nucleus and Globus Pallidus Internus Neurons in Patients With Parkinson’s Disease. The American Physiological Society. 2001.

Description of the Study: 13 patients underwent the implantation of deep brain stimulation electrodes in the subthalamic nucleus (STN), and 6 patients underwent a pallidotomy. Baseline readings were taken of these patients and then apomorphine was administered to determine the effect on “off” symptoms in Parkinson’s patients in the STN and the globus pallidus (Gpi). The doses of apomorphine used were 2.5 mg- 8 mg. The activity of neurons was measured with a single- unit microelectrode for an average of 15 minutes. Neuronal activity was also measured before, during, and after apomorphine wore off.

Results: A significant decrease in the overall firing rates of Gpi neurons (p<0.01) occurred after the administration of apomorphine. The overall firing rate of neurons in the STN (p=0.68) did not change significantly. Four patients did experience significantly lower rates than the “off” period and baseline rates (p<0.05). Other significant findings in the study included the reduction in the percentage of cells with tremor- related activities (19%-6%, STN; 14%-0%, Gpi), reduction in firing rate of STN tremor- related activities (p<0.05), and decreased proportion of STNs (7%) and Gpis (4%) that responded to passive movement of >2 joints after apomorphine administration.

Limitations: Some major limitations of this study include the use of a small sample of patients, lack of a separate control group, lack of blinding, and lack of randomization.

Conclusion: The study does demonstrate that apomorphine is effective for the acute symptomatic treatment of episodes of hypomobility in patients with Parkinson’s disease, and may work by attenuating neurons in the STN and Gpi.

Citation: Dewey R.B., et al. A randomized, Double- blind, Placebo- Controlled Trial of Subcutaneously Injected Apomorphine for Parkinsonian Off-State Events. Arch Neurol 2001 Sep:58; 1385-92.

Study Design: Prospective, randomized, double- blind, placebo- controlled, parallel group trial.

Description of Study: A total of twenty nine patients with advanced Parkinson’s disease were randomly assigned apomorphine or a pH matched placebo in this study. The study consisted of two phases. Phase I involved inpatient observation of doses that were titrated upwards to reverse an “off” state achieved by withholding antiparkinsonian medication coverage overnight. Phase II involved a one month period of outpatient observation of apomorphine efficacy when administered by patients and their caregivers. The number of “off” episodes was established prior to phase I at baseline. The subcutaneous doses used were titrated to 2 mg- 10 mg in this study. Changes in the United Parkinsonian Disease Rating Scale motor scores twenty minutes after apomorphine administration, and the percentage of injections used to successfully abort an “off” episode in the outpatient setting were measured.

Results: A significant difference was found between the reduction in the mean inpatient United Parkinsonian Disease Rating Scale motor scores in the apomorphine group and the placebo group (62% and 1%; p<0.001). There was also a significant difference found between the mean percentage of outpatient injections resulting in successful abortion of off- state events in the apomorphine group (95%) and the placebo group (23%) p<0.001. A correlation between inpatient response and outpatient efficacy was also found to be significant (p<0.001).

Limitations: The calculated power of the study was 87%, and the sample size was small.

Conclusion: The study was able to demonstrate that apomorphine is effective in reducing “off” episodes in advanced Parkinson’s patients.

Citation: Pietz K., et al. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry 1998;65:709-16.

Description of the Study: Patients were included in the study if they fulfilled the criteria for idopathic Parkinson’s disease, and had positive levadopa and apomorphine responses. A total of 49 patients were enrolled in the study and received treatment for 3- 66 months with either subcutaneous morphine or by continuous infusion. Patients started treatment one month after entering the study, and were admitted to the hospital for 2-5 weeks for apomorphine therapy. Peroral antiparkinsonian treatment was assessed and recorded during this time period prior to apomorphine use. An apomorphine test was performed on all patients to determine their responsiveness, onset of effect, duration of effect, and side effects. Doses used in the apomorphine test started with 0.5-1.0 mg and were titrated upward by the same amount. The maximum total amount allowed in one day was 6 mg. Patients received either continuous infusion or intermittent subcutaneous injection based on personal preference. The group of patients who received the continuous injection were assessed after a mean of 20.2 and 54.0 months, and the patient who received the intermittent subcutaneous injection were assessed after a mean of 10.2 and 42.2 months. When patients started the intermittent subcutaneous apomorphine treatment no changes were made in the antiparkinsonian medications, and half of the apomorphine test dose was administered and titrated up until optimal effect was reached. Patients received injections of apomorphine at the start of every “off” period and repeated the dose after 15 minutes if there was no effect. The levodopa doses were reduced by 30-50% in the continuous infusion group, and received apomorphine at a rate of 1 mg/h, which was titrated up by no more than 1 mg/h/dy until optimal effect was achieved. Patient’s motor status was recorded every 30 minutes prior to treatment and for 4-8 hours at each evaluation. Patients were also assessed using the Hoehn and Yahr, Schwab and England, and the Obeso dyskinesia scale at baseline and each follow up. A global impression scale was also completed by the patients and examiner at each follow up visit.

Results: The daily time spent in “off” episodes was significantly reduced from 50% to 25.0% (p<0.001), and the percentage reduction of “off” time correlated (r=0.71) with how much of the day patients spent in “off” episodes before apomorphine demonstrating that patients with more “off” episode time improved more. Of the 25 patients who received continuous infusion apomorphine 17 had a significant reduction in time spent in “off” episodes (p<0.001). The median Hoehn and Yahr staging scores improved in both “on” (before 3.0, with 4.0; p=0.02) and “off” (before 4.5, with 4.0; p<0.001) episodes with the use of apomorphine. Improvements in “on” episodes were seen in 10/25 patients, and improvements in “off” episodes were seen in 19/25 patients.

Limitations: The study lacks a control group receiving oral antiparkinsonian medications limiting the ability to compare apomorphine with existing antiparkinsonian treatments. The study also is limited by the lack of randomization of the patients to treatment groups.

Conclusion: Apomorphine significantly reduces the amount of time spent in “off” episodes, and is effective in treating patients with severe Parkinson’s disease.

Adverse effects: Yawning 40%, Dyskinesias 35%, Drowsiness/Somnolence 35%, Nausea/Vomiting 30%, Dizziness/Postural hypotension 20%, Rhinorrhea 20%, Angina 15%, Hallucination/Confusion 10%, Edema 10%.^1,2,3,4 The following occurred in 5% of patients: injection site complaint, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, pneumonia, confusion, sweating, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.^1,2,3,4

Drug Interactions: Serotonin antagonists: Hypotension and loss of consciousness may occur when apomorphine is given with ondestron, granisetron, dolasetron, palonosetron, and alosetron.^1,3,4 The concomitant administration of apomorphine with antihypertensives/vasodilators may lead to hypotension, myocardial infarction, pneumonia, falls, bone/joint injuries.^1,3,4 These side- effects may be due to excessive hypotension.^1,3,4 Dopamine antagonists such as phenothiazines, butyrophenone, thioxanthenes, and metoclopramid, may cause decreased efficacy of apomorphine by inhibiting its agonist activity.^1,3,4

Dosing/Administration: Apokyn is for subcutaneous administration only, and non- serotonin antagonist antiemetic should be used.^1,3,4 The manufacturer recommends initiating antiemetic therapy with trimethobenzamide three days prior to apokyn therapy, and continued for the first two months.¹ Therapy with apokyn should be initiated at a dose of 0.2 mg and titrated up in 1 mg increments based on the effectiveness and tolerance to a maximum dose of 0.6 mL.^1,3,4 If the patient tolerates but does not respond to the 2 mg test dose a second dose of 4 mg may be used.^1,3,4 If the patient tolerates and is able to respond to the 4 mg test dose the starting dose should be 2 mg as needed for “off” episodes, and may be increased by 1 mg increments every few days up to a maximum dose of 6 mg.^1,3,4 If the patient does not tolerate the 4 mg test dose a third test dose of 3 mg should be used.^1,3,4 If the 3 mg dose can be tolerated the starting dose should be 2 mg as needed for “off” episodes increased in 1 mg increments to a maximum of 3 mg.^1,3,4 Both supine and standing blood pressures should be taken before and after the administration of each dose.¹ Caution should be used in patients with hepatic impairment due to an increased C_max and AUC.¹ The starting dose and testing dose should be reduced to 0.1 mg in patients with renal impairment.^1,3,4,5 Currently dosages have not been established for pediatric patients because the safety and efficacy of the drug has not been studied in this patient population.^1,3,4 Dosages in the geriatriac population are the same as the usual adult dosage.^1,3,4

Conclusion: Overall apomorphine is effective for relieving “off” episodes occurring in severe Parkinson’s disease, and improving patient quality of life. The drug should only be used as an adjunct and not for monotherapy for Parkinson’s disease.