AHFS Class:

• Nonergot-derivative Dopamine Receptor Agonists 28:36.20.08

Generic Name(s):

• Apomorphine Hydrochloride

Chemical Name:

• 5,6,6a,7-Tetrahydro-6-methyl-4 H -dibenzo[ de , g ]quinoline-10,11-diol hydrochloride

Molecular Formula:

• C₁₇H₁₇NO₂ • HCl • ½H₂O

Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist.1,4

Parkinson Disease

Apomorphine hydrochloride injection is used subcutaneously for the acute, intermittent management of episodes of motor fluctuations (i.e., “off” episodes, including both end-of-dose “wearing off” and unpredictable “on-off” episodes) associated with advanced parkinson disease.1,2,3,4,5,8,9,11,12,13,14 The drug is used as an adjunct to other antiparkinsonian agents (e.g., levodopa, dopamine receptor agonists).1,2,5,8,11 Apomorphine is designated an orphan drug by FDA for this use.6

Efficacy of apomorphine for this indication has been established in 3 randomized, controlled studies in patients with advanced parkinson disease (average duration of illness: 11.3 years) who were being treated with levodopa and at least one other antiparkinsonian agent, usually an oral dopamine receptor agonist.1,2,5,8,11 One of the three studies was conducted in patients who did not have prior exposure to apomorphine and two were conducted in patients who had received apomorphine therapy for at least 3 months immediately prior to study enrollment.1,2,5,8 In these studies, the primary efficacy measurement was change in part III (motor performance) of the Unified Parkinson's Disease Rating Scale (UPDRS).1,5,8 Use of apomorphine (administered as intermittent subcutaneous injections) was associated with a substantial reduction in the UPDRS motor score in all 3 studies.1,2,5,8 In the randomized study conducted in patients who did not have prior exposure to apomorphine, use of apomorphine was associated with a 62% improvement in UPDRS score; in addition, apomorphine aborted 95% of “off” episodes during 4 weeks of therapy.5,11

Studies have demonstrated that the efficacy of apomorphine is comparable to that of levodopa for the treatment of motor symptoms of parkinson disease.126 Following subcutaneous administration, apomorphine provides rapid relief of parkinsonian symptoms, usually within 10-20 minutes, but has a short duration of action (about 60 minutes).1,2,5,8,12 Therefore, the drug is used principally as a rescue treatment for patients experiencing sudden wearing-off episodes despite optimized treatment with oral antiparkinsonian agents; there is some evidence that apomorphine may increase the risk of dyskinesia.123,124,126,157

Although not FDA-labeled for use as a continuous subcutaneous infusion†, apomorphine has been used safely and effectively in this manner; results of several studies, including a randomized, double-blind, placebo-controlled study, have shown that subcutaneous infusion of apomorphine can substantially reduce “off” time in patients with persistent motor fluctuations not controlled by optimized oral therapies.123,124,125,126

Administration

Apomorphine hydrochloride is administered by subcutaneous injection using a multi-dose pen on an "as-needed" basis.1 Injections may be administered into the abdomen, thigh, or upper arm; injection sites should be rotated.1 Apomorphine also has been administered as a continuous subcutaneous infusion† via a portable pump.123,124,125,126

Apomorphine hydrochloride should not be given IV because of the possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism).1 (See IV Administration under Warnings/Precautions: Warnings, in Cautions.)

To minimize nausea and/or vomiting associated with apomorphine therapy, an antiemetic (i.e., trimethobenzamide hydrochloride 300 mg orally 3 times daily) should be administered beginning 3 days prior to initiation of apomorphine therapy and continuing for the first 2 months of therapy or until tolerance develops.1,11 However, antiemetic agents that selectively inhibit type 3 serotonergic receptors (5-HT₃; e.g., granisetron, ondansetron, palonosetron) or dopamine receptors (e.g., metoclopramide, phenothiazines) should not be used.1,4 (See Drug Interactions.)

Doses of apomorphine should be spaced at least 2 hours apart.1

Dosage

Dosage of apomorphine hydrochloride is expressed in terms of the salt.1

Dosage of apomorphine hydrochloride must be individualized according to the patient's response and tolerance.1

Dosing instructions for the patient or their caregiver should always be expressed in mL to minimize dosing errors.1

Parkinson Disease

The dose of apomorphine hydrochloride must be titrated based on efficacy and tolerance.1 An initial test dose of 0.2 mL (2 mg) of apomorphine hydrochloride should be administered in a medical setting where blood pressure can be closely monitored by a health-care provider; the test dose should be administered while the patient is experiencing an “off” episode.1 Induction of an “off” episode can be facilitated by withholding the patient's antiparkinsonian agents overnight.1 Both supine and standing blood pressures should be measured prior to and at 20, 40, and 60 minutes after administration of the test dose.1 Patients who develop clinically important orthostatic hypotension in response to the initial 0.2-mL (2-mg) test dose should not be considered candidates for apomorphine therapy.1 If the 0.2-mL (2-mg) dose is effective and well tolerated, this dose may be used on an as-needed, outpatient basis to reverse “off” episodes; if necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days on an outpatient basis.1

For patients who tolerate but do not respond to the initial 0.2-mL (2-mg) test dose, a second test dose of 0.4 mL (4 mg) may be administered at the next observed “off” period, but no sooner than 2 hours after the initial test dose.1 Both supine and standing blood pressures should be measured prior to and at 20, 40, and 60 minutes after administration of the test dose.1 If this dose is effective and well tolerated, a 0.3-mL (3-mg) dose may be used on an as-needed, outpatient basis to reverse “off” episodes.1 If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days on an outpatient basis.1

If the patient responds to but does not tolerate a test dose of 0.4 mL (4-mg), a third test dose of 0.3 mL (3 mg) may be administered during a separate “off” period, but no sooner than 2 hours after the 0.4-mL (4-mg) test dose.1 Both supine and standing blood pressures should be measured prior to and at 20, 40, and 60 minutes after administration of the test dose.1 If the 0.3-mL (3-mg) dose is well tolerated and effective, a 0.2-mL (2-mg) dose may be used on an as-needed, outpatient basis to reverse “off” episodes.1 If the 0.2-mL (2-mg) dose is tolerated, the dose may be increased, if necessary, to 0.3 mL (3 mg) after a few days.1 In such a patient, the dose ordinarily should not be increased to 0.4 mL (4 mg) on an outpatient basis.1

Apomorphine hydrochloride doses exceeding 0.6 mL (6 mg) have not been shown to result in additional therapeutic effect and are not recommended.1 In addition, there is limited experience with administration of more than 5 doses per day or total daily doses exceeding 2 mL (20 mg).1

Safety and efficacy of a second dose of apomorphine hydrochloride during the same hypomobility episode in patients who did not respond to the initial dose have not been established.1 Therefore, no more than one dose of apomorphine hydrochloride should be administered for the treatment of a single “off” episode.1 A repeat dose should not be administered sooner than 2 hours after the last dose.1

If apomorphine therapy has been interrupted for more than 1 week and reinitiation of the drug is not contraindicated, therapy should be reinitiated at a dose of 0.2 mL (2 mg) and gradually titrated to effect.1

Special Populations

The manufacturer recommends an initial test dose and subsequent starting dose of 0.1 mL (1 mg) in patients with mild or moderate renal impairment.1 (See Renal Impairment under Warnings/Precautions: Special Populations, in Cautions.)

The manufacturer makes no special dosage recommendations for patients with hepatic impairment.1

Contraindications

Concomitant use with selective 5-HT₃ receptor antagonists (e.g., alosetron, dolasetron, granisetron, ondansetron, palonosetron).1 (See Drug Interactions.)

Known hypersensitivity to apomorphine hydrochloride or any ingredient in the formulation (e.g., sodium metabisulfite).1

Warnings/Precautions

Warnings

IV Administration

Serious adverse events (thrombus formation, pulmonary embolism) have occurred following IV administration of apomorphine.1,14 Intravascular thrombosis, believed to be secondary to the formation of apomorphine crystals and requiring cardiothoracic surgical intervention, has been reported in at least 3 patients receiving IV apomorphine.1,14 Apomorphine should not be administered IV.1

Nausea and Vomiting

Severe nausea and vomiting can be expected with recommended doses of apomorphine and concomitant use of an antiemetic is recommended.1 (See Dosage and Administration: Administration.) Almost all patients who participated in clinical trials in the US received trimethobenzamide; antiemetics other than trimethobenzamide were not evaluated in these trials.1,16 Despite use of trimethobenzamide in clinical trials, nausea and vomiting were reported in 31 and 11%, respectively, of apomorphine-treated patients.1 Trimethobenzamide has been shown to reduce the incidence of nausea and vomiting during the first 4 weeks of apomorphine treatment, but can increase the risk of somnolence, dizziness, and falls.1 Therefore, the benefit of such antiemetic treatment should be balanced against these risks, and the duration of therapy should be limited to the shortest amount of time necessary to control nausea and vomiting (generally no longer than 2 months).1

Concomitant use of apomorphine with antiemetics that selectively inhibit 5-HT₃ receptors is contraindicated and concomitant use with antiemetics that inhibit dopamine receptors should be avoided.1 (See Drug Interactions.)

Symptomatic Hypotension

Dopamine agonists appear to impair systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dosage escalation.1 Orthostatic hypotension can also be a manifestation of parkinson disease.123 Orthostatic hypotension, hypotension, and/or syncope were reported in approximately 11% of patients receiving apomorphine in clinical studies; these adverse effects were observed during initiation of apomorphine therapy as well as during long-term treatment.1

Patients receiving apomorphine should be monitored for signs and symptoms of orthostatic hypotension, particularly during dosage escalation.1 Because of additive hypotensive effects, concomitant use of alcohol is not recommended.1 Patients taking other vasodilators or antihypertensive agents should be monitored closely for hypotension and orthostatic hypotension during concomitant use of apomorphine.1 (See Drug Interactions.)

Prolongation of QT Interval

Apomorphine is associated with a risk of QT-interval prolongation at doses greater than 6 mg; torsades de pointes has not been observed to date.1 The use of apomorphine doses greater than 6 mg does not provide additional clinical benefit and should be avoided.1

The risks versus benefits should be considered in patients with risk factors for prolonged QT interval (e.g., those with congenital or known prolongation of the QT interval, those with bradycardia or hypokalemia or hypomagnesemia, and those receiving concomitant therapy with drugs that prolong the QT_c interval).1

Falls

Patients with parkinson disease are at risk of falling as a result of underlying postural instability and autonomic instability.1 In addition, patients may be at increased risk of falling as a result of the simultaneous effects of apomorphine on blood pressure and mobility.1 In clinical trials, 30% of patients had events that could be considered falls and about 5% of patients had falls that were considered serious.1

A symptom complex resembling the neuroleptic malignant syndrome (NMS; elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with abrupt withdrawal, dosage lowering, or changes in antiparkinsonian therapy.1

Hallucinations

Hallucinations were reported in about 14% of patients receiving apomorphine in clinical studies.1

During postmarketing experience, other new or worsening mental status and behavioral changes (e.g., paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, delirium) have been reported during therapy or after initiating or increasing the dosage of apomorphine.1 Other antiparkinsonian agents can produce similar effects.1

Use of apomorphine is generally not advised in patients with a major psychotic disorder.1 In addition, concomitant use with antipsychotic agents may exacerbate parkinsonian symptoms and decrease effectiveness of apomorphine.1

Falling Asleep During Activities of Daily Living and Somnolence

Patients receiving apomorphine have reported falling asleep while engaged in activities of daily living.1 Although somnolence is commonly associated with apomorphine, these patients perceived no warning signs and believed they were alert immediately prior to the event.1

Falling asleep while engaged in activities of daily living is thought to always occurs in a setting of preexisting somnolence although patients may not give such a history.1 Therefore, it is recommended that clinicians continually reassess patients for drowsiness or sleepiness especially because some incidents of sudden sleep onset occurred well after the start of apomorphine therapy.1 Clinicians also should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1 Prior to initiation of therapy, patients should be advised of the possibility that they may develop drowsiness and asked about any factors that may increase the risk of somnolence during apomorphine therapy (e.g., concomitant sedating drugs, the presence of sleep disorders).1 If a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), apomorphine generally should be discontinued.1 If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate this adverse effect.1

Cardiovascular Effects

Angina, myocardial infarction, cardiac arrest, and/or sudden death have been reported in 4% of patients receiving apomorphine.1 Angina and myocardial infarction occurred in some patients in close proximity to apomorphine dosing (within 2 hours); cardiac arrest and sudden death occurred at times unrelated to dosing in some patients.1

Apomorphine may exacerbate coronary and cerebral ischemia as a result of its effect on blood pressure.1 The drug should be used with extreme caution in patients with known cardiovascular and cerebrovascular disease.1 If patients develop signs and symptoms of coronary or cerebral ischemia, the continued use of apomorphine should be carefully evaluated.1

Abuse Potential

There are postmarketing reports of apomorphine abuse, which consisted of patients taking increasing doses of the drug in order to achieve an euphoric state.1,11 Escalation of apomorphine dose beyond the prescribed frequency has been reported in patients who attempt to avoid all symptoms of an “off” episode.1 However, a withdrawal syndrome has not been observed.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., urticaria, rash, pruritus, angioedema) caused by apomorphine or the sulfite excipient have been reported.1 The commercially available formulation of apomorphine hydrochloride injection contains sodium metabisulfite, which can cause serious allergic-type reactions in certain susceptible individuals.1,10 The overall prevalence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis.1,10 Sulfite sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.1,10

General Precautions

Dyskinesia

Apomorphine may cause or exacerbate dyskinesias.1 Dyskinesia or worsening of dyskinesia was reported in 24% of patients and resulted in discontinuance of the drug in 2% of patients in clinical studies.1

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, uncontrolled spending, binge eating, other intense urges) and the inability to control these urges have been reported in some patients receiving dopaminergic agents.1 In some cases, urges stopped when dosage was reduced or the drug was discontinued.1

Consider reducing dosage or discontinuing therapy if a patient develops such urges.1 (See Advice to Patients.)

Hyperpyrexia and Confusion

A symptom complex resembling the neuroleptic malignant syndrome (NMS; elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with abrupt withdrawal, dosage reduction, or changes in antiparkinsonian therapy.1

Fibrotic Complications

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy reported in some patients treated with ergot-derivative dopamine receptor agonists.1 Although these adverse effects presumably are related to the ergoline structure of these compounds, the possibility exists that nonergot-derived drugs that increase dopaminergic activity such as apomorphine may induce similar changes.1

Priapism

May cause prolonged painful erections.1 Severe priapism may require surgical intervention.

Ocular Effects

Retinal degeneration has been observed in albino rats given dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies) and in rats exposed to high-intensity light given these agents for shorter periods; however, retinal degeneration was not observed in a 2-year carcinogenicity study in albino mice or in rats or monkeys given these agents for 1 year.1 Apomorphine has not been evaluated in carcinogenicity studies; however, apomorphine is expected to cause similar ocular effects in animals.1 Although the clinical importance of these findings has not been established, the presumed mechanism of action of the effect may be applicable to all vertebrates (e.g., disk shedding).1,16

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of apomorphine in pregnant women.1 In animal reproduction studies, an increased incidence of neonatal deaths and cardiovascular malformations was observed at clinically relevant doses associated with maternal toxicity.1

Lactation

It is not known whether apomorphine is distributed into milk; effects of the drug on the breast-fed infant or on milk production also are not known.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for apomorphine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of apomorphine have not been established in pediatric patients.1

Geriatric Use

An increased incidence of confusion, hallucinations, serious adverse events (life-threatening events or events resulting in hospitalization and/or increased disability), falls, cardiovascular events, respiratory disorders, and GI events has been observed in geriatric individuals relative to younger adults.1

Hepatic Impairment

Systemic exposure to apomorphine is increased in patients with mild to moderate hepatic impairment; the drug should be used with caution in such patients.1 Apomorphine has not been evaluated systematically in patients with severe hepatic impairment.1

Renal Impairment

The initial dose of apomorphine hydrochloride should be reduced in patients with mild to moderate renal impairment.1,16 (See Dosage and Administration: Special Populations.) Apomorphine has not been evaluated systematically in patients with severe renal impairment.1 Studies have not been conducted in patients undergoing dialysis.16

Common Adverse Effects

Common adverse effects of apomorphine include yawning, dyskinesias, nausea and/or vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, and pallor.1

Drugs that Prolong QT Interval

Additive effects on QT-interval prolongation can occur if apomorphine is used concomitantly with other drugs that can prolong the QT interval.1 (See Prolongation of QT Interval under Warnings/Precautions: Warnings, in Cautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions are unlikely.1

5-HT3 Receptor Antagonists

Profound hypotension with loss of consciousness can occur if apomorphine is used concomitantly with 5-HT₃ receptor antagonists (e.g., ondansetron).1 Concomitant use is contraindicated.1

Dopamine Antagonists

Efficacy of apomorphine may be reduced when the drug is used concomitantly with certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide.1

Patients with major psychosis receiving certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) should be treated with dopamine agonists only if the benefits outweigh the risks.1

Hypotensive Agents and Vasodilators

Additive hypotensive effects may occur; caution is advised during concomitant use.1

Hypotension, myocardial infarction, pneumonia, serious falls, and bone and joint injuries have been reported more frequently in patients receiving concomitant antihypertensive drugs or vasodilators.1 The mechanism underlying many of these events is unknown, but may be associated with hypotension.1 (See Symptomatic Hypotension under Warnings/Precautions: Warnings, in Cautions.)

The hypotensive effects of apomorphine are increased with concurrent use of alcohol or sublingual nitroglycerin.1 Concomitant use of apomorphine and alcohol should be avoided.1 If nitroglycerin is used in a patient receiving apomorphine, the patient should be instructed to lie down before and after taking nitroglycerin.1

CNS Depressants

Additive sedative and hypotensive effects may occur if apomorphine is used concomitantly with alcohol; therefore, concomitant use of alcohol as well as alcohol use following administration of apomorphine should be avoided. 1

Additive sedative effects may occur if apomorphine is used concomitantly with other CNS depressants.1

Levodopa/Carbidopa

Additive effects on motor response have been demonstrated when apomorphine is used concomitantly with levodopa/carbidopa and this combination is used to therapeutic advantage in the management of “off” episodes.1 Pharmacokinetic interaction is unlikely.1

Catechol- O -Methyltransferase (COMT) Inhibitors

Pharmacokinetic interaction is unlikely.1,7 The manufacturer of entacapone advises caution if the drug is used concomitantly with apomorphine.17,18

Description

Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist that is structurally and pharmacologically related to dopamine.1,3 In in vitro studies, apomorphine hydrochloride demonstrated a higher affinity for the dopamine D₄ receptor than for dopamine D₂, D₃, or D₅ receptors.1 Apomorphine hydrochloride binds with moderate affinity to α-adrenergic (α_1D, α_2B, α_2C) receptors but has little or no affinity for dopamine D₁ receptors, serotonergic (5-HT_1A, 5-HT_2A, 5-HT_2B, 5-HT_2C) receptors, β₁- or β₂-adrenergic receptors, or histamine H₁ receptors.1

The exact mechanism of action of apomorphine hydrochloride in the treatment of parkinson disease has not been fully elucidated but may involve stimulation of postsynaptic dopamine D₂ receptors within the caudate-putamen in the brain.1 Apomorphine has been shown to improve motor function in an animal model of parkinson disease.1 In particular, apomorphine attenuates the motor deficits associated with neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ([MPTP])-induced lesions in the ascending nigrostriatal dopaminergic pathway in primates.1

Routes of apomorphine metabolism in humans are not known.1 Potential metabolic routes include sulfation, N -demethylation, glucuronidation, and oxidation.1 Apomorphine undergoes rapid auto-oxidation in vitro.1 Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine.1 In vitro studies have suggested that apomorphine may be metabolized by COMT.17,19,20 Data from in vivo studies indicate that apomorphine is not metabolized by COMT.1,20

Advice to Patients

Importance of taking apomorphine only as prescribed.1

Importance of instructing patient and/or caregiver regarding proper dosage and administration of apomorphine, including detailed instruction in the use of the dosing pen, in patients whose clinician has determined that the drug can safely and effectively be self-administered in the patient's home by the patient, family member, or other responsible caregiver.1

Advise that hallucinations, hypotension, and other adverse effects (e.g., injection site reactions) may occur.1

Risk of postural hypotension with or without dizziness, nausea, syncope, or sweating.1 Advise not to rise rapidly after prolonged sitting or lying down, especially during the first few weeks of therapy.1

Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving apomorphine and advising them of the importance of reporting such urges.1

Risk of somnolence and the possibility of falling asleep during activities of daily living; necessity of exercising caution when driving or operating machinery.1

Importance of informing clinicians if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, riding in a car as a passenger) occur at any time during apomorphine therapy.1 Patients should not drive or participate in potentially dangerous activities until their clinician has been notified.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. US WorldMeds. Apokyn^® (apomorphine hydrochloride) injection prescribing information. Louisville, KY; 2019 Dec.

2. Stacy M. Apomorphine: North American clinical experience. Neurology . 2004; 62(Suppl 4):S18-21.

3. Dewey RB Jr. Management of motor complications in Parkinson's disease. Neurology . 2004; 62(Suppl 4):S3-7. [PubMed 15037664]

4. Anon. FDA approves Apokyn^® for the acute treatment of episodes of immobility in Parkinson's patients. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2004 Apr 21.

5. Dewey RB Jr, Hutton JT, LeWitt PA et al. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol . 2001; 58:1385-92. [PubMed 11559309]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2004 Aug 16. [Web]

7. Zijlmans JCM, Debilly B, Rascol O et. al. Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson's disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study. Mov Disord . 2004; 19:1006-11. [PubMed 15372589]

8. Sherry JH, Guyton PJ, Van Lunen B et al. Continued efficacy and safety of subcutaneous injections of apomorphine in the treatment of off episodes in patients with Parkinson's disease. Neurology . 2003; 60(Suppl 1): A81.

9. Hughes AJ, Bishop S, Kleedorfer B et al. Subcutaneous apomorphine in Parkinson's disease: response to chronic administration for up to five years. Mov Disord . 1993; 8:165-70. [PubMed 8474483]

10. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use: warning statement. [Docket No. 84N-0113] Fed Regist . 1985; 50:47558-63.

11. Anon. Apomorphine (Apokyn) for advanced Parkinson's disease. Med Lett Drugs Ther . 2005; 47:7-8. [PubMed 15647705]

12. Factor SA. Literature review: intermittent subcutaneous apomorphine therapy in Parkinson's disease. Neurology . 2004; 62(Suppl 4):S12-7. [PubMed 15037666]

13. Mylan Bertek Pharmaceuticals Inc. Apokyn^® (apomorphine hydrochloride) monograph. Research Triangle Park, NC; 2004 May 26.

14. Koller W, Stacy M. Other formulations and future considerations for apomorphine for subcutaneous injection therapy. Neurology . 2004; 62(Suppl 4):S22-6.

15. AHFS Drug Information 1990. McEvoy, GK, ed. Apomorphine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 1990:1652-3.

16. Mylan Bertek Pharmaceuticals, Overland Park, KS: Personal communication.

17. Novartis . Comtan^® (entacapone) tablets prescribing information. East Hanover, NJ; 2000 Mar.

18. Novartis. Stalevo^® 50, Stalevo^® 100, Stalevo^® 150 (carbidopa, levodopa, and entacapone) tablets prescribing information. East Hanover, NJ; 2004 Jan.

19. Le Witt P. Subcutaneously administered apomorphine: pharmacokinetics and metabolism. Neurology . 2004; 62(Suppl 4):S8-11.

20. van der Geest R, van Laar T, Kruger PP et al. Pharmacokinetics, enantiomer interconversion, and metabolism of R -apomorphine in patients with idiopathic Parkinson's disease. Clin Neuropharmacol . 1998; 21:159-68. [PubMed 9617507]

123. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA . 2014 Apr 23-30; 311:1670-83. [PubMed 24756517]

124. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA . 2020; 323:548-560. [PubMed 32044947]

125. Katzenschlager R, Poewe W, Rascol O et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol . 2018; 17:749-759. [PubMed 30055903]

126. Carbone F, Djamshidian A, Seppi K et al. Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs . 2019; 33:905-918. [PubMed 31473980]

157. . Drugs for Parkinson's disease. Med Lett Drugs Ther . 2017; 59:187-194. [PubMed 29136401]