Apomorphine (DB00714): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Safety Profile

Executive Summary

Apomorphine is a potent, non-ergoline, non-selective dopamine agonist that occupies a specialized niche in the management of advanced Parkinson's disease (PD). Its primary, well-established clinical role is the acute, intermittent treatment of hypomobility, or "off" episodes, which are debilitating motor fluctuations that occur despite optimized oral therapy.[1] The name "Apomorphine" is a historical artifact derived from its synthesis from morphine; however, it is crucial to recognize that the molecule possesses no opioid receptor activity and is devoid of narcotic properties, a point of potential clinical confusion that requires clarification.[3]

The clinical utility of apomorphine is defined by a challenging pharmacokinetic profile, characterized by poor oral bioavailability and a very short elimination half-life.[3] These limitations have been the primary drivers of pharmaceutical innovation, leading to the development of non-oral formulations designed to bypass first-pass metabolism and provide clinically meaningful drug exposure. These include a subcutaneous injection (Apokyn) for rapid rescue, a sublingual film (Kynmobi) as a non-invasive alternative, and, most recently, a continuous subcutaneous infusion device (Onapgo) for stable, long-term motor control.[5]

The therapeutic value of apomorphine is predicated on a significant efficacy-tolerability trade-off. Its efficacy in reversing motor "off" states is comparable to that of levodopa, the gold standard in PD treatment, but with a much more rapid onset of action.[7] This benefit is counterbalanced by a substantial adverse effect profile, most notably severe nausea and vomiting, which necessitates prophylactic antiemetic therapy, as well as orthostatic hypotension, somnolence, and potential neuropsychiatric effects.[9] The recent U.S. Food and Drug Administration (FDA) approval of the Onapgo continuous infusion device signals a paradigm shift in its application, moving beyond a reactive "rescue" role to a proactive strategy of continuous dopaminergic stimulation, positioning it as a less invasive alternative to other advanced therapies for managing motor fluctuations.[11]

Introduction and Historical Context

Defining Apomorphine

Apomorphine is a small molecule classified as an aporphine alkaloid.[3] Pharmacologically, it functions as a potent, non-selective dopamine agonist, meaning it binds to and activates dopamine receptors in the central nervous system.[3] Its primary therapeutic application is in the field of neurology, specifically for the management of motor complications in patients with advanced Parkinson's disease.[1]

The Morphine Misnomer: A Critical Clarification

The nomenclature of apomorphine is a significant source of potential clinical confusion and warrants immediate clarification. The name is a historical remnant derived from its original synthesis method, first described in the 19th century, which involved the dehydration and molecular rearrangement of morphine by heating it with a concentrated acid.[3] The prefix "apo-" denotes this derivative relationship, indicating that it "[comes] from morphine".[3]

Despite this etymological link, it is clinically paramount to understand that apomorphine is pharmacologically distinct from morphine and all other opioids. It does not contain the morphine chemical skeleton, does not bind to any opioid receptors, and possesses none of the analgesic or narcotic properties associated with opioids.[3] This distinction is fundamental to its safe and appropriate clinical use, as any association with opioid pharmacology could lead to incorrect assumptions regarding its mechanism, therapeutic effects, or potential for opioid-like dependence. The name itself may present an educational barrier for both clinicians and patients, necessitating a proactive explanation to disentangle its chemical history from its actual dopaminergic mechanism of action.

Historical Trajectory

Apomorphine's history dates back to its first synthesis in the mid-19th century.[1] Its potent pharmacological effects were recognized early, leading to its initial application in Parkinson's disease as far back as 1884.[1] However, for much of its history, its most prominent use was as a powerful emetic, a property derived from its strong stimulation of the chemoreceptor trigger zone in the brainstem.[3]

Beyond its emetic action, apomorphine has been explored for a variety of other conditions. In the late 19th and early 20th centuries, it was used in addiction medicine as a treatment for alcoholism, with some practitioners believing it could relieve anxiety and craving.[3] More recently, its centrally-acting dopaminergic effects led to investigations into its potential for treating erectile dysfunction.[3] While these historical applications underscore the drug's potent and diverse pharmacological activity, its modern therapeutic role has been firmly established and refined within the management of advanced Parkinson's disease.

Physicochemical and Structural Characteristics

Chemical Identity and Nomenclature

Apomorphine is identified by a comprehensive set of chemical names and registry numbers that ensure its precise identification across scientific and regulatory databases.

• IUPAC Name: (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol [3]
• CAS Number: 58-00-4 [3]
• DrugBank ID: DB00714 [1]
• Synonyms: (-)-10,11-dihydroxyaporphine, (R)-(-)-Apomorphine, l-Apomorphine [1]
• Other Identifiers: PubChem CID: 6005; ChEMBL ID: CHEMBL53; KEGG ID: D07460.[3]

Molecular Formula and Weight

The empirical formula for the apomorphine free base is C17​H17​NO2​.[13] This corresponds to a molecular weight of approximately 267.32 g/mol.[13] The elemental composition of the molecule is approximately 76.38% carbon, 6.41% hydrogen, 5.24% nitrogen, and 11.97% oxygen.[23]

Structure and Stereochemistry

Apomorphine possesses a complex, rigid, three-dimensional tetracyclic structure characteristic of an aporphine alkaloid.[13] A critical feature of its molecular architecture is the presence of a chiral center, which gives rise to two stereoisomers (enantiomers). The biological activity of apomorphine resides almost exclusively in the

(R)-enantiomer, which is also designated as the levorotatory (-) form.[3] This stereospecificity is a fundamental principle of its pharmacology, as the shape of the

(R)-enantiomer allows it to bind effectively to and activate its target dopamine receptors, whereas the (S)-enantiomer is largely inactive.

Physical Properties and Stability

In its solid state, apomorphine appears as white to off-white crystals or powder, sometimes forming hexagonal plates.[13] It is soluble in alcohol and chloroform and slightly soluble in water, with a reported water solubility of 20 g/L.[13]

A key physicochemical characteristic of apomorphine is its instability. The molecule is susceptible to oxidation, particularly when exposed to light and air, which causes it to decompose and turn a characteristic green color.[16] This degradation is more rapid in aqueous solutions.[23] This inherent instability has significant practical implications for its formulation and clinical use. To improve stability, the drug is most commonly formulated as its hydrochloride hemihydrate salt (CAS Number: 41372-20-7), which is the preferred form for pharmaceutical commerce.[16] Furthermore, this instability necessitates that apomorphine solutions be visually inspected for clarity and color before administration; any solution that is cloudy, green, or contains particulate matter should be discarded.[2]

Table 1: Key Identifiers and Physicochemical Properties of Apomorphine

Property	Value	Source(s)
DrugBank ID	DB00714	1
CAS Number	58-00-4	3
IUPAC Name	(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol	3
Molecular Formula	C17​H17​NO2​	13
Molecular Weight	267.32 g/mol	16
Appearance	White to off-white crystalline powder	13
Melting Point	195 °C (decomposes)	16
Water Solubility	20 g/L	16
SMILES	CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3	13
InChIKey	VMWNQDUVQKEIOC-CYBMUJFWSA-N	13

Comprehensive Pharmacological Profile

Mechanism of Action and Receptor Binding

Primary Mechanism in Parkinson's Disease

The therapeutic efficacy of apomorphine in Parkinson's disease stems from its function as a direct-acting dopamine agonist.[2] The motor symptoms of PD are caused by the progressive degeneration of dopaminergic neurons in the substantia nigra, leading to a profound deficiency of dopamine in the striatum (caudate-putamen).[4] Apomorphine's structure partially resembles that of dopamine, allowing it to bypass the degenerating presynaptic neurons and directly stimulate postsynaptic dopamine receptors within these critical motor control regions.[4] This stimulation effectively mimics the action of the missing endogenous dopamine, thereby restoring signaling in the nigrostriatal pathway and alleviating motor deficits, which manifests clinically as a rapid reversal of "off" state hypomobility.[1]

Receptor Subtype Affinity and Non-Dopaminergic Activity

Apomorphine's pharmacology is complex, characterized by its broad, non-selective binding profile across multiple receptor families.

• Dopamine Receptors: It is a potent agonist with high affinity for the D2-like receptor subfamily, which includes the D2, D3, and D4 subtypes.[1] It also demonstrates agonist activity at D1-like receptors (D1 and D5), though to a lesser extent.[3] The stimulation of D2 receptors in the caudate-putamen is considered the principal mechanism for its anti-parkinsonian effects.[1]
• Serotonin (5-HT) Receptors: Apomorphine exhibits high-affinity antagonism at 5-HT2 receptors (subtypes A, B, and C).[3] Additionally, it acts as an agonist at several 5-HT1 receptor subtypes (1A, 1B, and 1D).[1] This serotonergic activity likely contributes to some of its neuropsychiatric side effects.
• Adrenergic Receptors: The drug also functions as an antagonist at α-adrenergic receptors and an agonist at α2-adrenergic subtypes (2A, 2B, and 2C).[3] Its interaction with these receptors is the primary cause of its significant cardiovascular side effects, particularly orthostatic hypotension.

This multifaceted receptor interaction profile explains why apomorphine is both a highly effective motor agent and a drug with a challenging side-effect profile.

Table 2: Receptor Binding Affinity Profile of Apomorphine

Receptor Family	Receptor Subtype	Nature of Interaction	Affinity (Ki​ in nM)	Source(s)
Dopamine	D2	Agonist	High (not specified)	1
	D3	Agonist	High (not specified)	1
	D4	Agonist	High (not specified)	1
	D5	Agonist	High (not specified)	1
	D1	Agonist	Moderate (less than D2)	3
Serotonin	5-HT2A	Antagonist	High (not specified)	3
	5-HT2B	Antagonist	High (not specified)	3
	5-HT2C	Antagonist	High (not specified)	3
	5-HT1A	Agonist	High (not specified)	1
	5-HT1B	Agonist	High (not specified)	1
	5-HT1D	Agonist	High (not specified)	1
Adrenergic	α2A, α2B, α2C	Agonist/Antagonist	High (not specified)	1
	α1D	Agonist	Moderate (not specified)	12
Other	β-adrenergic, H1, mACh	Negligible	>10,000	3

Other Neurobiological Effects

Beyond direct receptor binding, apomorphine has been shown to exert other potentially beneficial neurobiological effects. Both the (R)- and (S)-enantiomers are potent iron chelators and radical scavengers, which may have neuroprotective implications given the evidence of excess iron accumulation at sites of neurodegeneration in PD.[3] It has also been shown to decrease the breakdown of dopamine in the brain and upregulate certain neural growth factors, particularly Nerve Growth Factor (NGF).[3]

Pharmacodynamics

The pharmacodynamic effects of apomorphine are a direct consequence of its receptor binding profile and are characterized by a rapid onset and short duration of action.[1]

• Therapeutic Motor Effects: The primary and desired effect is the potent stimulation of motor function. This is achieved through the activation of dopamine receptors in the nigrostriatal, limbic, hypothalamic, and pituitary systems, leading to a rapid and reliable transition from a hypomobile "off" state to a mobile "on" state.[2]
• Emetic Effect: A powerful and near-universal pharmacodynamic effect is emesis (nausea and vomiting). This is not a peripheral gastrointestinal effect but a centrally mediated one, caused by the potent stimulation of D2 receptors located in the chemoreceptor trigger zone (CTZ) of the medulla oblongata, which in turn activates the adjacent vomiting center.[3] This effect is so potent that it is a major dose-limiting factor and necessitates the use of prophylactic antiemetics.
• Cardiovascular Effects: Apomorphine consistently produces cardiovascular effects, most notably hypotension and orthostatic hypotension (a drop in blood pressure upon standing).[1] This is a result of its combined dopaminergic vasodilation and α-adrenergic antagonism.[3] Furthermore, apomorphine has been shown to cause a dose-related prolongation of the QTc interval on an electrocardiogram, which is a serious pharmacodynamic concern as it can increase the risk of potentially fatal cardiac arrhythmias like Torsades de Pointes.[1]
• Central Nervous System (CNS) Effects: As a potent CNS-acting agent, apomorphine can induce a range of other effects. Somnolence (drowsiness), including sudden and irresistible episodes of sleep, is a common and serious risk.[1] Its powerful stimulation of dopaminergic and serotonergic pathways can also lead to hallucinations, confusion, and other psychotic-like behaviors, as well as impulse control disorders such as pathological gambling or hypersexuality.[1]

Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion - ADME)

The clinical application of apomorphine is fundamentally governed by its challenging pharmacokinetic properties. Its poor oral bioavailability and extremely rapid clearance are the central scientific problems that have dictated its entire developmental trajectory, from its initial use as an injection to the modern advent of sublingual films and continuous infusion devices. This evolution represents a multi-decade effort to engineer delivery systems that can overcome these inherent biological limitations.

• Absorption: The route of administration dramatically alters apomorphine's absorption and bioavailability.
• Oral: When taken orally, apomorphine is poorly absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism in the liver, resulting in very low and unreliable bioavailability.[3] This route is considered clinically unfeasible.
• Subcutaneous (SC): In stark contrast, SC injection bypasses the gastrointestinal tract and first-pass metabolism, providing 100% bioavailability.[3] Absorption from subcutaneous tissue is rapid and complete, with peak plasma concentrations ( Tmax​) achieved within 5 to 10 minutes in most patients, correlating directly with its rapid onset of clinical effect.[3]
• Sublingual: The sublingual film offers a non-invasive alternative. It provides slower absorption compared to the SC route, with a median Tmax​ of approximately 40-45 minutes. Its relative bioavailability is significantly lower than SC injection, at approximately 17%.[32]
• Distribution: Apomorphine is a lipophilic (fat-soluble) molecule, a property that allows it to readily cross the blood-brain barrier and reach its target receptors in the CNS.[3] It has a large apparent volume of distribution, indicating extensive distribution into tissues throughout the body.[1] In the bloodstream, it is highly bound to plasma proteins, with an estimated 99.9% bound to human serum albumin.[1]
• Metabolism: Apomorphine is subject to rapid and extensive metabolism, primarily occurring in the liver.[3] It is a high-clearance drug, with a clearance rate of 3–5 L/kg/hr.[3] The metabolism is complex and proceeds through multiple pathways:
• Phase I Metabolism: N-demethylation is carried out by several cytochrome P450 enzymes, including CYP2B6, CYP2C8, CYP3A4, and CYP3A5.[1]
• Phase II Metabolism: Conjugation reactions are a major route of metabolism. These include O-glucuronidation by various UGT enzymes and sulfation by SULT enzymes (1A1, 1A2, 1A3, 1E1, and 1B1).[1] For the sublingual formulation, approximately 60% of the dose is eliminated as a sulfate conjugate.[1]
• Other Pathways: Auto-oxidation is also a significant metabolic pathway.[3]
• Excretion: Due to its extensive metabolism, only a very small fraction of the administered dose (approximately 0.3–4%) is excreted unchanged in the urine.[3] The metabolites, such as apomorphine glucuronide and norapomorphine glucuronide, are the primary forms eliminated from the body.[1] The terminal elimination half-life is very short, ranging from 30 to 60 minutes for SC and intravenous routes, and approximately 1.7 hours for the sublingual formulation.[1] This rapid clearance is responsible for the brief duration of its clinical effect following a single dose.

Table 3: Comparative Pharmacokinetic Parameters of Apomorphine Formulations

Parameter	Subcutaneous (SC) Injection (e.g., Apokyn)	Sublingual Film (e.g., Kynmobi)	Continuous SC Infusion (e.g., Onapgo)
Bioavailability	~100%	~17% (relative to SC)	~100%
Time to Peak Plasma Concentration (Tmax​)	5-10 minutes	~40-45 minutes	Not applicable (maintains steady state)
Elimination Half-Life (t1/2​)	~30-60 minutes	~1.7 hours	~30-60 minutes
Key Clinical Correlate	Rapid-onset "rescue" for acute "off" episodes	Slower-onset, non-invasive "rescue"	Proactive prevention of "off" episodes; stable motor control
Source(s)	3	1	5

Clinical Efficacy and Therapeutic Applications

FDA-Approved Indication: Management of "Off" Episodes in Advanced Parkinson's Disease

The primary and sole FDA-approved indication for apomorphine is the acute, intermittent treatment of hypomobility "off" episodes in patients with advanced Parkinson's disease.[1] These "off" episodes are a hallmark of advancing disease, where the effectiveness of oral medications like levodopa diminishes between doses.[4] They manifest as periods of returning motor symptoms, such as difficulty moving, walking, and speaking, and can occur predictably as a dose wears off ("end-of-dose wearing off") or unpredictably ("on-off" fluctuations).[2]

The clinical evidence supporting apomorphine's efficacy for this indication is robust. For decades, numerous open-label studies and clinical experience demonstrated that intermittent subcutaneous apomorphine injections provide rapid, reliable, and effective relief from "off" periods.[7] Its efficacy on motor symptoms has been shown to be virtually indistinguishable from that of levodopa, but with the distinct advantages of a much faster onset of action (typically within 12 minutes) and bypassing the gastrointestinal system, which is beneficial for patients with delayed gastric emptying (gastroparesis).[7]

More recently, the pivotal TOLEDO clinical trial (NCT02006121) provided high-level, Class 1 evidence for the efficacy of continuous subcutaneous apomorphine infusion.[34] This randomized, double-blind, placebo-controlled study demonstrated that continuous infusion led to a clinically and statistically significant reduction in daily "off" time, averaging approximately 2.5 hours less "off" time per day compared to baseline, versus only a 35-minute reduction with placebo.[34] This was accompanied by a significant increase in "on" time without troublesome dyskinesia.[34] These findings were instrumental in the FDA approval of the Onapgo infusion device and solidified apomorphine's role as a cornerstone therapy for managing motor fluctuations in advanced PD.

Historical and Investigational (Off-Label) Uses

Throughout its long history, apomorphine's potent and diverse pharmacological actions have led to its investigation for several other conditions, though these are not FDA-approved indications.

• Erectile Dysfunction (ED): Apomorphine was investigated as a centrally-acting treatment for ED. It was one of the few agents explored in an orally active (buccal or sublingual) formulation for this purpose.[17] The mechanism is believed to involve the stimulation of dopamine receptors in the hypothalamus that are involved in penile erection.[17] While it can induce erections in both normal and impotent men, its clinical utility has been limited by a narrow therapeutic window and a high incidence of dose-limiting side effects, particularly nausea, emesis, and drowsiness.[13]
• Addiction Medicine: Historically, apomorphine was used in the treatment of addiction to alcohol and heroin.[3] In the early 20th century, some practitioners used low, non-emetic doses to reduce alcohol cravings.[3] Later, it gained notoriety through the writings of William S. Burroughs, who anecdotally championed it as a "metabolic cure" for heroin addiction.[3] However, despite this history and some renewed research interest, there is no robust clinical trial evidence to support its efficacy or safety as a treatment for opiate addiction.[3]
• Emetic: Due to its powerful and reliable stimulation of the chemoreceptor trigger zone, apomorphine has been used to induce vomiting, primarily in cases of acute poisoning.[16] This application is more common in veterinary medicine, particularly for dogs that have ingested toxins.[16] Its use as an emetic in humans has been largely replaced by other interventions.
• Disorders of Consciousness: A novel and emerging area of research is the use of apomorphine for patients with severe brain injuries. A currently ongoing randomized, double-blind, placebo-controlled clinical trial (APODoC, NCT05213169) is investigating whether continuous subcutaneous apomorphine infusion can improve behavioral responses in patients with disorders of consciousness, such as those in an unresponsive wakefulness syndrome or a minimally conscious state.[37] This represents a promising new frontier for apomorphine's application beyond movement disorders.

Formulations, Dosage, and Clinical Administration

The challenging pharmacokinetics of apomorphine have necessitated the development of specialized non-oral formulations. In the United States, three distinct formulations are available, each designed to meet different clinical needs in the management of Parkinson's disease "off" episodes.[5]

Intermittent Subcutaneous Injection (Apokyn)

• Indication: Apokyn is indicated for the acute, intermittent "rescue" treatment of "off" episodes.[5]
• Dosage and Titration: Treatment must be initiated with a test dose administered under medical supervision to assess both efficacy and tolerability, particularly for orthostatic hypotension. The starting test dose is typically 1-2 mg (0.1-0.2 mL) injected subcutaneously into the abdomen, upper arm, or thigh.[2] The dose is then titrated upwards in subsequent "off" episodes until a satisfactory clinical response is achieved. The usual maintenance dose ranges from 2 mg to 6 mg, administered as needed. Doses should be separated by at least two hours, and the maximum recommended single dose is 6 mg.[9]

Sublingual Film (Kynmobi)

• Indication: Kynmobi is also indicated for the acute, intermittent treatment of "off" episodes, offering a non-invasive rescue option.[5]
• Dosage and Administration: The available dose strengths range from 10 mg to 30 mg. Similar to the injection, treatment begins with a 10 mg test dose supervised by a healthcare provider.[39] The dose can be titrated upwards in 5 mg increments in subsequent "off" episodes to find the optimal dose. The dose range for as-needed use is 10 mg to 30 mg, with a maximum of five doses per day and a minimum of two hours between doses.[6] Administration is critical: the patient should moisten their mouth with water, then place the whole film under the tongue and allow it to dissolve completely (about 3 minutes) without cutting, chewing, or swallowing.[39]

Continuous Subcutaneous Infusion (Onapgo)

• Indication: Onapgo is designed to provide more consistent, continuous control of motor fluctuations in patients with advanced PD, moving beyond intermittent rescue to proactive prevention.[5]
• Dosage and Administration: This therapy utilizes a small, wearable infusion pump that delivers apomorphine subcutaneously for up to 16 hours during the waking day.[5] The dosage is highly individualized and determined through a careful titration process. A typical starting regimen involves a continuous infusion rate of 1 mg/hour, which is gradually increased by 0.5 to 1 mg/hour increments based on response and tolerability.[38] The device also allows for the administration of as-needed extra bolus doses (typically 0.5 to 2 mg) to treat any breakthrough "off" symptoms, with no more than three extra doses per day.[38]

The Critical Role of Antiemetic Co-therapy

A universal and critical aspect of apomorphine administration, regardless of formulation, is the management of its profound emetic effects.

• Rationale: Severe nausea and vomiting are extremely common, particularly upon initiation of therapy.[2] This centrally-mediated side effect can be dose-limiting and lead to treatment discontinuation if not managed proactively.
• Recommended Agent and Regimen: Premedication with an antiemetic is standard practice. The recommended agent is trimethobenzamide, typically at a dose of 300 mg taken three times daily.[2] This antiemetic therapy should be started three days before the first dose of apomorphine is administered.[9]
• Duration and Risks of Antiemetic Use: While essential initially, many patients develop a tolerance to apomorphine's emetic effects over time. Therefore, treatment with trimethobenzamide should only be continued as long as necessary and generally for no longer than two months.[2] This is important because long-term use of trimethobenzamide in conjunction with apomorphine has been shown to increase the incidence of other adverse effects, including somnolence, dizziness, and falls.[2]
• Contraindicated and Discouraged Antiemetics: A crucial safety warning pertains to the co-administration of apomorphine with serotonin 5-HT3 receptor antagonists (e.g., ondansetron, granisetron). This combination is absolutely contraindicated due to reports of profound hypotension and loss of consciousness.[6] Additionally, antiemetics that are also dopamine antagonists (e.g., metoclopramide, prochlorperazine) should be avoided, as they can directly counteract the therapeutic effect of apomorphine and worsen the underlying symptoms of Parkinson's disease.[6]

Safety, Tolerability, and Risk Management

The use of apomorphine is predicated on a careful balance between its potent efficacy and its significant tolerability burden. A thorough understanding of its adverse effect profile, contraindications, and interactions is essential for safe clinical practice.

Adverse Effect Profile

Apomorphine is associated with a wide range of adverse effects, stemming from its potent stimulation of dopaminergic, serotonergic, and adrenergic pathways.

• Very Common and Common Adverse Reactions: The most frequently encountered side effects are direct extensions of its pharmacology.
• Gastrointestinal: Severe nausea and vomiting are nearly universal upon initiation and are the most common reasons for dose limitation or discontinuation.[3]
• Nervous System: Drowsiness (somnolence), including sudden onset of sleep during daily activities, is very common and poses a significant safety risk.[10] Dizziness, often related to postural hypotension, is also frequently reported.[10] Dyskinesias (uncontrolled, involuntary movements), or the worsening of pre-existing dyskinesias, are common, particularly in patients also taking levodopa.[9] Yawning and rhinorrhea (runny nose) are also very common.[10]
• Cardiovascular: Hypotension and orthostatic hypotension are common.[10]
• Local Reactions: For subcutaneous formulations, injection site reactions such as bruising, itching, swelling, and the formation of hard nodules are very common.[5] For the sublingual film, oral and pharyngeal side effects like mucosal irritation, swelling, and pain are common.[1]
• Serious Adverse Reactions: While less frequent, apomorphine can cause severe and potentially life-threatening adverse events.
• Psychiatric: Hallucinations, confusion, and the development of psychotic-like behaviors (e.g., paranoia, delusions, agitation) can occur.[5] Impulse control disorders, such as pathological gambling, compulsive shopping, or hypersexuality, are a known class effect of dopamine agonists and have been reported with apomorphine.[5]
• Cardiovascular: Serious coronary events, including angina, myocardial infarction, and sudden death, have been reported.[9] Apomorphine also causes QTc interval prolongation, which carries a risk of serious cardiac arrhythmias.[9] Syncope (fainting) can also occur.[10]
• Hematologic: Hemolytic anemia, a condition where red blood cells are prematurely destroyed, is a rare but serious potential side effect that can occur at any time during treatment and may require hospitalization.[9]
• Genitourinary: Priapism, a prolonged and painful erection lasting more than four hours, is a rare but serious adverse effect that constitutes a medical emergency.[5]
• Other: A symptom complex resembling neuroleptic malignant syndrome (high fever, muscle rigidity, confusion) can occur upon abrupt withdrawal or rapid dose reduction of apomorphine.[9]

Table 4: Summary of Common and Serious Adverse Reactions to Apomorphine by System Organ Class

System Organ Class	Very Common (>10%)	Common (1-10%)	Serious (Frequency Varies)
Gastrointestinal	Nausea, Vomiting 10	Dry mouth, Constipation, Diarrhea 10	-
Nervous System	Drowsiness/Somnolence, Dyskinesias, Yawning, Dizziness 10	Headache, Insomnia, Fall, Vertigo 10	Sudden onset of sleep, Syncope, Withdrawal-emergent hyperpyrexia 9
Psychiatric	-	Hallucination, Confusion, Depression, Anxiety 10	Psychotic-like behavior, Impulse control disorders 5
Cardiovascular	-	Postural Hypotension, Chest Pain/Angina, Edema, Congestive heart failure, Palpitations 10	Myocardial infarction, Cardiac arrest, QTc prolongation, Torsades de Pointes, Thrombus formation (with IV use) 9
General/Administration Site	Injection site reactions (bruising, nodules, itching), Rhinorrhea 5	Fatigue, Weakness, Sweating 10	Hypersensitivity/Anaphylaxis, Fibrotic complications 9
Hematologic	-	Ecchymosis (bruising) 10	Hemolytic anemia 9
Genitourinary	-	Urinary tract infection 10	Priapism 5
Oral (Sublingual Film)	-	Oropharyngeal pain, swelling, irritation 1	Severe oral mucosal reactions 1

Contraindications, Warnings, and Precautions

Absolute Contraindications

The use of apomorphine is strictly contraindicated in the following situations:

• Concomitant use with 5-HT3 Antagonists: Co-administration with serotonin 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, palonosetron, alosetron) is absolutely contraindicated. This combination has been associated with profound hypotension and loss of consciousness.[6]
• Known Hypersensitivity: Patients with a known hypersensitivity or allergic reaction to apomorphine or any of its excipients are contraindicated. The subcutaneous injection formulation (Apokyn) contains sodium metabisulfite, which can cause severe allergic reactions, including anaphylaxis and life-threatening asthma attacks, particularly in patients with a history of asthma or sulfite sensitivity.[2]

Warnings and Precautions

A number of significant warnings and precautions accompany the use of apomorphine:

• Intravenous Administration: Apomorphine must never be administered intravenously. IV administration can cause the drug to crystallize in the veins, leading to serious thrombus formation and potentially fatal pulmonary embolism.[3]
• Cardiovascular Risks: Use with caution in patients with underlying cardiovascular or cerebrovascular disease, as the drug's hypotensive effects may exacerbate ischemia.[44] Patients with risk factors for QTc prolongation (e.g., bradycardia, hypokalemia, hypomagnesemia, congenital long QT syndrome) should be treated with caution.[44]
• Psychiatric Conditions: Apomorphine should generally not be used in patients with a major psychotic disorder, as it can exacerbate psychosis.[44]
• Renal and Hepatic Impairment: Dose adjustments and increased monitoring are required for patients with mild to moderate renal or hepatic impairment due to altered drug clearance. It has not been studied in severe renal or hepatic disease.[28]
• Elderly Patients: Elderly patients may be more susceptible to CNS and cardiovascular side effects, including confusion, hallucinations, and falls, requiring cautious use.[45]

Clinically Significant Drug and Disease Interactions

Drug-Drug Interactions

Apomorphine has numerous clinically significant drug interactions, primarily pharmacodynamic in nature.

• Antihypertensives, Vasodilators, and Alcohol: Concomitant use with these agents can lead to additive hypotensive effects, increasing the risk of dizziness, syncope, and falls. Alcohol should be avoided entirely.[6] The combination with sublingual nitroglycerin requires particular caution.[6]
• Dopamine Antagonists: Drugs that block dopamine receptors, such as typical antipsychotics (e.g., haloperidol) and certain antiemetics (e.g., metoclopramide), will directly antagonize the therapeutic effect of apomorphine and may worsen PD symptoms. Their use should be avoided.[6]
• CNS Depressants: Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, sedatives, alcohol) can result in additive sedation and an increased risk of somnolence and sudden sleep onset.[46]
• QTc-Prolonging Drugs: Caution is advised when apomorphine is used with other medications known to prolong the QTc interval (e.g., certain antiarrhythmics, antipsychotics, antibiotics), as this may increase the risk of serious cardiac arrhythmias.[6]

Table 5: Clinically Significant Drug Interactions with Apomorphine

Interacting Drug/Class	Potential Effect	Clinical Recommendation	Source(s)
5-HT3 Antagonists (e.g., ondansetron, granisetron)	Profound hypotension, loss of consciousness	Contraindicated	6
Dopamine Antagonists (e.g., neuroleptics, metoclopramide)	Diminished therapeutic efficacy of apomorphine; worsening of PD symptoms	Avoid concomitant use	6
Alcohol	Increased risk and severity of hypotension and CNS depression (somnolence)	Avoid concomitant use	6
Antihypertensives & Vasodilators (e.g., nitroglycerin)	Additive hypotensive effects, increased risk of syncope and falls	Monitor blood pressure closely; advise patient on managing orthostasis	6
Other CNS Depressants (e.g., benzodiazepines, opioids, sedatives)	Additive sedation, increased risk of sudden sleep onset	Use with caution; monitor for excessive somnolence	1
Other QTc-Prolonging Drugs (e.g., certain antiarrhythmics, antipsychotics)	Additive QTc prolongation, increased risk of Torsades de Pointes	Use with caution; consider risk/benefit, especially in high-risk patients	6

Drug-Disease Interactions

The use of apomorphine requires careful consideration of the patient's underlying medical conditions:

• Psychotic Disorders: May exacerbate psychosis.[44]
• Cardiovascular/Cerebrovascular Disease: Hypotensive effects can worsen ischemia.[44]
• Hypotension/Orthostatic Hypotension: Apomorphine can significantly worsen this condition.[44]
• Sleep Disorders/Hypersomnia: Can cause or worsen somnolence and lead to sudden sleep attacks.[44]
• Asthma: The sulfite excipient in the injection formulation can trigger allergic reactions.[44]
• Dyskinesia: Can cause new or worsen pre-existing dyskinesia.[44]

Regulatory and Developmental Landscape

FDA Regulatory History

Apomorphine has a long history of clinical use, but its regulatory journey in the United States for the treatment of Parkinson's disease is more recent and reflects the evolution of modern drug development and approval standards.

• 2004: The U.S. Food and Drug Administration (FDA) granted its initial approval for apomorphine under the brand name Apokyn. This approval was for the subcutaneous injection formulation, specifically for the acute, intermittent treatment of "off" episodes in advanced PD.[12]
• 2020: The FDA approved Kynmobi, a sublingual film formulation of apomorphine. This provided the first non-invasive "rescue" option for patients, addressing the need for an alternative to injections.[39]
• 2025: A significant milestone was reached with the FDA approval of Onapgo on February 3-4, 2025.[11] Onapgo is a continuous subcutaneous infusion device. Its path to approval was lengthy, involving an initial New Drug Application (NDA) submission for the device (then known as SPN-830) in September 2020, followed by several resubmissions and regulatory updates before finally receiving approval.[12] This approval was heavily based on the strength of the TOLEDO clinical trial data.

A notable aspect of apomorphine's history is the significant time lag between its widespread clinical use in Europe and the generation of Class 1 evidence required for U.S. approval. Continuous subcutaneous apomorphine infusion has been an established therapy in Europe for decades, with its use guided largely by extensive clinical experience and open-label studies.[35] However, its approval in the U.S. required the higher evidentiary standard of a large-scale, prospective, randomized, placebo-controlled trial—the TOLEDO study, published in 2018.[34] This gap illustrates how differing regulatory philosophies and evidence requirements can impact the global availability of therapies, even those with a long history of perceived efficacy.

Recent and Ongoing Clinical Research

The development of apomorphine continues to evolve, with research focused on improving delivery methods, confirming long-term safety, and exploring new therapeutic applications.

• Pivotal Trials for Continuous Infusion: The approval of Onapgo was underpinned by the TOLEDO study (NCT02006121), which provided the definitive Phase 3, randomized, controlled data demonstrating the superiority of continuous apomorphine infusion over placebo in reducing "off" time.[34] The long-term safety and efficacy were further supported by the open-label InfusON study (NCT02339064), which followed U.S. patients for up to 52 weeks and confirmed sustained reductions in "off" time and improvements in "on" time.[11]
• Novel Formulations: The search for more convenient and less invasive delivery systems is a key area of research. A recent two-part clinical study (Trial NL9540) evaluated a novel, highly concentrated oromucosal solution (APORON). The study found that this formulation was well-tolerated and could achieve clinically relevant plasma concentrations comparable to a low-dose subcutaneous injection, suggesting it could be a user-friendly alternative to both injections and sublingual films.[54]
• Safety and Tolerability Studies: Research also focuses on better understanding and managing apomorphine's side effects. Post-hoc analyses of long-term studies with the sublingual film (CTH-301) have provided valuable insights into factors that predict treatment retention and tolerability, particularly in elderly patients, and have explored the impact of dose on the incidence of oropharyngeal side effects.[42] Other studies, such as a terminated pilot trial (NCT02230930), have investigated methods to manage the common apomorphine-induced skin reactions that occur with subcutaneous infusion.[41]
• Emerging Applications: As previously noted, the ongoing APODoC trial (NCT05213169) is exploring apomorphine's potential to treat disorders of consciousness, a significant expansion beyond its traditional use in movement disorders.[37]

Conclusion and Future Perspectives

Synthesis of Apomorphine's Clinical Profile

Apomorphine has firmly established its place in the therapeutic armamentarium for advanced Parkinson's disease as a potent and rapid-acting dopaminergic agent. It is an indispensable tool for managing refractory motor fluctuations that no longer respond adequately to conventional oral therapies. Its clinical profile is defined by a fundamental trade-off: its levodopa-comparable efficacy and rapid onset of action are balanced by a significant tolerability burden. The successful use of apomorphine is therefore contingent upon careful patient selection, meticulous dose titration, and proactive management of its predictable and often severe side effects, particularly nausea, hypotension, and somnolence.

The Evolving Role in Parkinson's Disease Therapy

The recent approval of a continuous subcutaneous infusion system (Onapgo) represents a significant evolution in the clinical application of apomorphine. This development marks a strategic shift in its use, transforming it from a purely reactive, "rescue" medication for acute "off" episodes into a proactive, continuous maintenance therapy aimed at preventing motor fluctuations from occurring. This positions apomorphine infusion as a viable, device-aided therapy that is less invasive than other advanced treatments such as Deep Brain Stimulation (DBS) or Levodopa-Carbidopa Intestinal Gel (LCIG). It provides a crucial intermediate option for patients with advancing disease who require more stable dopaminergic stimulation but may not be candidates for, or wish to undergo, more invasive surgical procedures.

Future Research Directions

The future of apomorphine therapy will likely focus on two primary goals: enhancing its tolerability and expanding its therapeutic applications. The ongoing quest for less invasive, more user-friendly, and better-tolerated formulations is a clear priority, as demonstrated by active research into novel delivery systems like oromucosal solutions. A formulation that could provide rapid onset of action without the need for injection and with a lower incidence of local or systemic side effects would represent a major advance.

Furthermore, there is growing interest in exploring the potential neuroprotective properties of apomorphine, such as its documented ability to chelate iron and upregulate nerve growth factor. While preliminary, these findings suggest a potential role beyond purely symptomatic treatment, which warrants further investigation. Finally, the exploration of apomorphine for other severe neurological conditions, such as its current investigation in patients with disorders of consciousness, signals a promising new frontier. The overarching objective of future research will be to continue harnessing the potent dopaminergic efficacy of this historic molecule while innovating to minimize the tolerability challenges that have historically limited its use.

Works cited

1. Apomorphine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 22, 2025, https://go.drugbank.com/drugs/DB00714
2. Apomorphine Injection: MedlinePlus Drug Information, accessed August 22, 2025, https://medlineplus.gov/druginfo/meds/a604020.html
3. Apomorphine - Wikipedia, accessed August 22, 2025, https://en.wikipedia.org/wiki/Apomorphine
4. Introduction - Clinical Review Report: Apomorphine (Movapo) - NCBI Bookshelf, accessed August 22, 2025, https://www.ncbi.nlm.nih.gov/books/NBK534022/
5. Apomorphine: Uses, Dosage, Side Effects, Warnings - Drugs.com, accessed August 22, 2025, https://www.drugs.com/apomorphine.html
6. Apomorphine: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 22, 2025, https://www.rxlist.com/apomorphine/generic-drug.htm
7. (PDF) Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations - ResearchGate, accessed August 22, 2025, https://www.researchgate.net/publication/335563569_Apomorphine_for_Parkinson's_Disease_Efficacy_and_Safety_of_Current_and_New_Formulations
8. Open-Label Study Assessment of Safety and Adverse Effects of Subcutaneous Apomorphine Injections in Treating "Off" Episodes in Advanced Parkinson Disease | Request PDF - ResearchGate, accessed August 22, 2025, https://www.researchgate.net/publication/23445930_Open-Label_Study_Assessment_of_Safety_and_Adverse_Effects_of_Subcutaneous_Apomorphine_Injections_in_Treating_Off_Episodes_in_Advanced_Parkinson_Disease
9. APOKYN® (apomorphine hydrochloride injection), for subcutaneous use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021264s021lbl.pdf
10. Apomorphine Injection: Package Insert / Prescribing Info - Drugs.com, accessed August 22, 2025, https://www.drugs.com/pro/apomorphine-injection.html
11. Second Under-the-Skin Infusion for Parkinson's Earns FDA Approval, accessed August 22, 2025, https://www.michaeljfox.org/news/second-under-skin-infusion-parkinsons-earns-fda-approval
12. Onapgo (apomorphine hydrochloride) FDA Approval History - Drugs ..., accessed August 22, 2025, https://www.drugs.com/history/onapgo.html
13. CAS 58-00-4: (-)-Apomorphine | CymitQuimica, accessed August 22, 2025, https://cymitquimica.com/cas/58-00-4/
14. CHEBI:48538 - apomorphine - EMBL-EBI, accessed August 22, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:48538
15. The Pharmacological Properties and Therapeutic Use of Apomorphine - MDPI, accessed August 22, 2025, https://www.mdpi.com/1420-3049/17/5/5289
16. Apomorphine - American Chemical Society, accessed August 22, 2025, https://www.acs.org/molecule-of-the-week/archive/a/apomorphine.html
17. apomorphine CAS#: 58-00-4 - ChemicalBook, accessed August 22, 2025, https://m.chemicalbook.com/ProductChemicalPropertiesCB8875448_EN.htm
18. The crystal and molecular structure of apomorphine hydrochloride hydrate - IUCr Journals, accessed August 22, 2025, https://journals.iucr.org/paper?S0567740873005534
19. Apomorphine Hydrochloride | C34H38Cl2N2O5 | CID 107882 - PubChem, accessed August 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Apomorphine-hydrochloride-hemihydrate
20. Apomorphine | C17H17NO2 - ChemSpider, accessed August 22, 2025, https://www.chemspider.com/Chemical-Structure.5783.html
21. Apomorphine - brand name list from Drugs.com, accessed August 22, 2025, https://www.drugs.com/ingredient/apomorphine.html
22. (R)-(−)-Apomorphine | CAS 58-00-4 | SCBT - Santa Cruz Biotechnology, accessed August 22, 2025, https://www.scbt.com/p/r-apomorphine-58-00-4
23. Apomorphine, accessed August 22, 2025, https://www.drugfuture.com/chemdata/apomorphine.html
24. KEGG DRUG: Apomorphine hydrochloride, accessed August 22, 2025, https://www.genome.jp/dbget-bin/www_bget?D02004+D07460
25. Apomorphine in the treatment of Parkinson's disease: a review - SciELO, accessed August 22, 2025, https://www.scielo.br/j/anp/a/Zfkx8CbQRHcTszzF39DvGYP/
26. go.drugbank.com, accessed August 22, 2025, https://go.drugbank.com/drugs/DB00714#:~:text=Apomorphine%20is%20a%20dopaminergic%20agonist,brain%20involved%20in%20motor%20control.&text=It%20has%20a%20short%20duration,are%20necessary%20for%20significant%20toxicity.
27. Apomorphine (Apokyn): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 22, 2025, https://www.webmd.com/drugs/2/drug-91232/apomorphine-subcutaneous/details
28. Apokyn, Onapgo (apomorphine) dosing, indications, interactions, adverse effects, and more, accessed August 22, 2025, https://reference.medscape.com/drug/apokyn-onapgo-apomorphine-343040
29. Apomorphine | Parkinson's UK, accessed August 22, 2025, https://www.parkinsons.org.uk/information-and-support/apomorphine
30. Peripheral pharmacokinetics of apomorphine in humans - Semantic Scholar, accessed August 22, 2025, https://www.semanticscholar.org/paper/Peripheral-pharmacokinetics-of-apomorphine-in-Gancher-Woodward/d651def42963fbd1743f0de73e5b932048d5a61b
31. Pharmacokinetics of apomorphine in Parkinson's disease - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/8748619/
32. Pharmacokinetics and Comparative Bioavailability of Apomorphine ..., accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/33991326/
33. Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson's disease - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/10511920/
34. Apomorphine, More Evidence for An Old Drug: A Key for Therapy Generalization? - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6384177/
35. Apomorphine Reduces Off Time for People with Advanced Parkinson's Disease - MDEdge, accessed August 22, 2025, https://www.mdedge.com/neurologyreviews/article/136411/parkinsons-disease/apomorphine-reduces-time-people-advanced
36. Insights on the Newly Approved Subcutaneous Infusion Therapy for ..., accessed August 22, 2025, https://www.neurologylive.com/view/insights-newly-approved-subcutaneous-infusion-therapy-parkinson-disease
37. Study Details | Apomorphine in Severe Brain-injured Patients | ClinicalTrials.gov, accessed August 22, 2025, https://www.clinicaltrials.gov/study/NCT05213169?term=APOMORPHINE&rank=4
38. Apomorphine Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 22, 2025, https://www.drugs.com/dosage/apomorphine.html
39. KYNMOBI (apomorphine hydrochloride) Label - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210875lbl.pdf
40. Apomorphine Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 22, 2025, https://www.drugs.com/sfx/apomorphine-side-effects.html
41. Treatment of Apomorphine-induced Skin Reactions: a Pilot Study | ClinicalTrials.gov, accessed August 22, 2025, https://www.clinicaltrials.gov/study/NCT02230930?term=AREA%5BBasicSearch%5D(Apomorphine%20Infusion)&rank=5
42. Insights into retention and safety/tolerability of apomorphine sublingual film in patients with Parkinson's disease and OFF episodes: post hoc analyses of a phase III, open-label study - PMC - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12181698/
43. Medical Information - APOKYN® (apomorphine HCI), accessed August 22, 2025, https://www.apokynhcp.com/hcp-resources/medical-information
44. Apomorphine Disease Interactions - Drugs.com, accessed August 22, 2025, https://www.drugs.com/disease-interactions/apomorphine.html
45. Apomorphine (sublingual route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/apomorphine-sublingual-route/description/drg-20489659
46. Apomorphine (subcutaneous route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/apomorphine-subcutaneous-route/description/drg-20068366
47. Apomorphine and Alcohol/Food Interactions - Drugs.com, accessed August 22, 2025, https://www.drugs.com/food-interactions/apomorphine.html
48. Apomorphine Hcl Food, Alcohol, Supplements and Drug Interactions - ScriptSave WellRx, accessed August 22, 2025, https://www.wellrx.com/apokyn/lifestyle-interactions/
49. FDA Approves First Subcutaneous Apomorphine Device for Parkinson Disease, accessed August 22, 2025, https://www.ajmc.com/view/fda-approves-first-subcutaneous-apomorphine-device-for-parkinson-disease
50. Supernus Announces SPN-830 Apomorphine Infusion Device NDA Accepted for Review by FDA, accessed August 22, 2025, https://ir.supernus.com/news-releases/news-release-details/supernus-announces-spn-830-apomorphine-infusion-device-nda-0
51. Apomorphine – Knowledge and References - Taylor & Francis, accessed August 22, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Apomorphine/
52. Clinical Trial of Apomorphine Subcutaneous Infusion in Patients With Advanced Parkinson's Disease (TOLEDO) - ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT02006121
53. Continuous, subcutaneous apomorphine infusion for Parkinson disease motor fluctuations: Results from the phase 3, long-term, open-label United States InfusON study - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/39973510/
54. Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients, accessed August 22, 2025, https://www.researchgate.net/publication/380401286_Clinical_trial_evaluating_apomorphine_oromucosal_solution_in_Parkinson's_disease_patients
55. Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11075157/
56. (PDF) Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study - ResearchGate, accessed August 22, 2025, https://www.researchgate.net/publication/379372301_Long-term_safety_tolerability_and_efficacy_of_apomorphine_sublingual_film_in_patients_with_Parkinson's_disease_complicated_by_OFF_episodes_a_phase_3_open-label_study