AHFS Class:

• Nonergot-derivative Dopamine Receptor Agonists 28:36.20.08

Generic Name(s):

• Apomorphine Hydrochloride

Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist.1,  2

Parkinson Disease

Apomorphine hydrochloride injection is used subcutaneously in adults for the 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 The drug is commercially available as a subcutaneous injection formulation and as a subcutaneous infusion formulation.1,  2 Apomorphine is designated an orphan drug by FDA for the treatment of on-off fluctuations associated with late-stage Parkinson disease.6

Clinical Experience

Efficacy of apomorphine as an intermittent subcutaneous injection (Apokyn^®) has been established in 3 randomized, controlled studies in patients with advanced Parkinson disease (average duration of illness: 11 years) who were being treated with levodopa and at least one other antiparkinsonian agent, usually an oral dopamine receptor agonist.1,  5,  8 One of the three studies was conducted in patients who did not have prior exposure to apomorphine and 2 were conducted in patients who received apomorphine therapy for at least 3 months immediately prior to study enrollment.1,  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,  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

Efficacy of apomorphine as a continuous subcutaneous infusion (Onapgo^®) has been established in a randomized, multicenter, double-blind, placebo-controlled trial (TOLEDO).2,  21 In the TOLEDO study, patients with Parkinson disease who had motor fluctuations during treatment with carbidopa/levodopa and other concomitant medications for Parkinson disease were randomized to receive a subcutaneous infusion of apomorphine (titrated to an individually optimized rate of 3-8 mg per hour, administered for approximately 16 hours of the waking day) or placebo.21 All patients received antiemetic prophylaxis prior to the infusion and were maintained on levodopa; adjustments to other Parkinson disease medications were also made when clinically indicated.2,  21 The infusion was initiated inpatient or outpatient over a period of 5-10 days; the dose could then be adjusted weekly through the end of week 4, then patients continued therapy for an 8-week maintenance period where the dose was unchanged.21 The primary measure of efficacy was the change in total daily “off” time from baseline to week 12, which the patients recorded in diaries; change in daily “on” time without troublesome dyskinesia was evaluated as a secondary outcome.2,  21

At baseline, patients enrolled in the TOLEDO trial were a mean age of 63.4 years old; 62% were male, 100% were white, and “off” episodes averaged ≥3 hours per day.2 All patients were taking oral levodopa (immediate- or extended-release) plus a dopa decarboxylase inhibitor and at least one additional concomitant treatment (dopamine agonist, 87%; catechol-O-methyltransferase [COMT] inhibitor, 58%; monoamine oxidase B [MAO-B] inhibitor, 40%; amantadine, 27%).2 At baseline, patients had a mean disease duration of 11.9 years in the apomorphine group versus 10.8 years in the placebo group.2

After 12 weeks, patients treated with apomorphine in the TOLEDO study had a substantially greater reduction in “off” time from baseline compared to those treated with placebo (-2.55 versus -0.90 hours, respectively; difference, -1.65 hours).2 Apomorphine was also associated with substantial increases in “on” time without troublesome dyskinesia compared to placebo (2.76 versus 1.12 hours; difference, 1.64 hours).2 A 52-week, open-label extension of the TOLEDO study found that these improvements in “off” and “on” time were sustained for up to 64 weeks.22

Clinical Perspective

To date, there are no therapies available to prevent or delay the progression of Parkinson disease; thus, treatment is largely symptomatic.23,  24 In patients with motor fluctuations who are early in the course of Parkinson disease, oral or transdermal treatments are preferred, with progression to parenteral and surgical techniques in patients with more advanced disease.24 Numerous oral therapies are available for initial management of motor symptoms in patients early in their disease; both levodopa and all dopamine agonists (ergot and non-ergot) improve motor symptoms in patients with early disease.23,  24 While less effective for treating motor symptoms, MAO-B inhibitors may also be used in patients with milder symptoms.23,  24 Choice of specific agent depends on the level of disability, potential adverse effects of treatment, and the need to prevent long-term motor complications (i.e., dyskinesias).23,  24 In patients with more advanced disease and bothersome motor fluctuations, parenteral medications or surgical procedures may be warranted.24 Guidelines from international experts suggest that intermittent subcutaneous administration of apomorphine is a clinically useful option in such patients.24 Continuous subcutaneous apomorphine was considered “likely efficacious”; however, full results from the TOLEDO study had not been available at the time of guideline publication.24

General

Patient Monitoring

• Measure blood pressure and pulse in the supine and standing position before and after administering subcutaneous injections of apomorphine (Apokyn^®).1
• When administering the test dose in patients receiving subcutaneous injections of apomorphine (Apokyn^®), both supine and standing blood pressures and pulse should be measured prior to and at 20, 40, and 60 minutes post-dose (and after 60 minutes if there is significant hypotension at 60 minutes).1 Patients who develop clinically important orthostatic hypotension in response to the initial test dose should not be considered candidates for apomorphine therapy.1
• Monitor for signs and symptoms of orthostatic hypotension during treatment with apomorphine, especially when the dosage is increased.1,  2

Premedication and Prophylaxis

• Treatment with trimethobenzamide 300 mg three times per day is recommended starting 3 days prior to the first dose of apomorphine and continuing as long as needed to control nausea and vomiting.1,  2 Treatment with trimethobenzamide is generally limited to ≤2 months due to an increased incidence of CNS adverse effects (e.g., somnolence, dizziness, and falls) in patients treated with both agents.1,  2

Dispensing and Administration Precautions

Handling and Disposal

• Apomorphine is classified as a hazardous drug by the Centers for Disease Control and Prevention National Institute for Occupational Safety and Health (NIOSH).400
• Because the Apokyn^® pen has markings in milliliters (mL), express the prescribed dose of Apokyn^® in mL to avoid confusion.1
• The prescribed dose of Onapgo^® should be expressed in “mg/hr” for the continuous dosage and “mg” for an extra dose.2

Other General Considerations

• Apomorphine continuous subcutaneous infusion (Onapgo^®) is not substitutable for apomorphine products intended for intermittent use.2 There is insufficient information about concomitant use of other apomorphine-containing products with Onapgo^®.2
• After initiating apomorphine, adjustment of other concomitant anti-Parkinson medications may be necessary.2

Administration

Apomorphine hydrochloride is available for administration as an intermittent subcutaneous injection (Apokyn^®) and a continuous subcutaneous infusion (Onapgo^®).1,  2

Apomorphine hydrochloride should not be given IV because of the possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism).1,  2

Apomorphine initiation and dose titrations should be performed under medical supervision; a caregiver or patient may administer subsequent doses following education and training if deemed appropriate by a healthcare provider.1,  2

Intermittent Subcutaneous Injection (Apokyn®)

Apomorphine hydrochloride (Apokyn^®) is administered by subcutaneous injection using a multi-dose pen or a disposable prefilled pen on an "as-needed" basis.1 Injections may be administered into the stomach area (at least 2 inches from the naval), upper thigh, or upper arm; injection sites should be rotated.1

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

Store apomorphine for subcutaneous injection (Apokyn^®) at 25°C; excursions are permitted between 15-30°C.1

Continuous Subcutaneous Infusion (Onapgo®)

Apomorphine is also available as a continuous subcutaneous infusion (Onapgo^®) that is administered via a portable pump.2 Refer to the Onapgo^® prescribing information for detailed instructions for use.2 Administer subcutaneously using aseptic technique into one of the following areas: the abdomen (at least 2 inches from the naval), top of thigh, or lower back.2 If the infusion site is being prepared by a caregiver or healthcare provider, the drug can also be administered in the upper back.2 Change the infusion site daily and avoid infusion into areas that are bruised, have bumps or nodules, or are irritated.2 Use a new single-dose cartridge and cartridge holder every day and discard any unused portion.2

Store apomorphine for continuous subcutaneous infusion (Onapgo^®) at 20-25°C; excursions are permitted between 15-30°C.2

Dosage

Dosage of apomorphine hydrochloride is expressed in terms of the salt.1,  2

Dosage of apomorphine hydrochloride must be individualized according to the patient's response and tolerance.1,  2

Parkinson Disease

Intermittent Subcutaneous Injection (Apokyn®)

The dose of apomorphine hydrochloride must be titrated based on efficacy and tolerance.1 An initial test dose of 0.1-0.2 mL (1-2 mg) of apomorphine hydrochloride should be administered in a medical setting where blood pressure and pulse can be closely monitored by a health-care provider; the test dose should be administered while the patient is experiencing an “off” episode.1 Consider a lower starting dose of 0.1 mL (1 mg) to mitigate the risk of nausea and vomiting.1 Patients who develop clinically important orthostatic hypotension in response to the initial test dose should not be considered candidates for apomorphine therapy.1 If the test 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 an initial 0.1 mL (1 mg) test dose, a second test dose of 0.2 mL (2 mg) may be administered at the next observed “off” period, but no sooner than 2 hours after the initial test dose.1 For patients who tolerate but do not respond to an 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 Patients who are unable to tolerate a 0.2 mL (2 mg) dose may require slow titration.1 If a 0.4 mL (4 mg) test dose is effective and well tolerated, a 0.3 mL (3 mg) initial maintenance 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 If the 0.3 mL (3 mg) dose is well tolerated and effective, a 0.2 mL (2 mg) initial maintenance 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

Continuous Subcutaneous Infusion (Onapgo®)

When administered via continuous subcutaneous infusion, the daily dosage of apomorphine hydrochloride is composed of a continuous dosage and additional dose(s) that are administered as needed.2 The dose of apomorphine hydrochloride must be titrated based on efficacy and tolerance.2 An initial continuous dosage (continuous infusion) of 1 mg/hr is recommended.2 Titrate the dosage up in increments of 0.5-1 mg/hr as needed.2 Adjustments to the dose can be made daily, or at longer intervals throughout the titration period.2 In clinical trials, the average continuous dosage of apomorphine was 4 mg/hr.2 The maximum dosage is 6 mg/hr administered over the waking day (e.g., 16 hours).2

In addition to the continuous dosage of apomorphine, extra doses may be administered: 1) upon starting in the morning; 2) upon continuous dosage restart following a break in use of ≥1 hour; or 3) as a supplement to the continuous dosage to manage uncontrolled “off” symptoms.2 A maximum of 3 extra doses may be administered per day over 16 hours; allow at least 3 hours between extra doses.2 Titrate the extra dose in increments of 0.5-1 mg based on clinical response and tolerability.2 Subsequent extra doses may be between 0.5-2 mg.2

If the patient routinely requires 3 extra doses per day, consider adjusting the continuous dosage.2 The maximum recommended daily dosage (including the continuous dosage and any extra doses administered) is 98 mg during the waking day (e.g., 16 hours).2

Sudden discontinuation or rapid dose reduction can cause increased severity of Parkinson disease motor symptoms; if possible, taper the dosage before discontinuing the drug.2

Special Populations

Hepatic Impairment

The manufacturer makes no special dosage recommendations for patients with hepatic impairment.1,  2 Exercise caution and closely monitor patients with mild or moderate hepatic impairment if apomorphine is administered.1,  2

Apomorphine has not been studied in patients with severe hepatic impairment.1,  2

Renal Impairment

For patients receiving apomorphine as an intermittent subcutaneous injection (Apokyn^®), 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

For patients receiving apomorphine as a continuous subcutaneous infusion (Onapgo^®), the manufacturer recommends an initial extra dose between 0.5-1 mg (not exceeding 1 mg) in patients with mild or moderate renal impairment.2 No dosage adjustment is needed for the continuous dose, maximum recommended daily dose, or subsequent extra doses after the initial extra dose.2

Apomorphine has not been studied in patients with severe renal impairment.1,  2

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1,  2 Cautious dosage selection is recommended, usually starting at the low end of the dosing range, due to the increased incidence of decreased hepatic, renal, or cardiac function and comorbid disease or other drug therapy in such patients.2

Contraindications

• Concomitant use with selective 5-HT₃ receptor antagonists (e.g., alosetron, dolasetron, granisetron, ondansetron, palonosetron).1,  2
• Known hypersensitivity or allergic reaction to apomorphine hydrochloride or any ingredient in the formulation (e.g., sodium metabisulfite).1,  2

Warnings/Precautions

Serious Adverse Reactions After IV Administration

Serious adverse events (thrombus formation and pulmonary embolism due to IV crystallization of apomorphine) have occurred following IV administration of apomorphine.1,  2

Apomorphine should not be administered IV.1,  2

Nausea and Vomiting

Nausea and vomiting, which may be severe, can occur with apomorphine.1,  2 Most patients in clinical trials received premedication with trimethobenzamide; antiemetics other than trimethobenzamide were not evaluated in these trials.1,  2

Despite use of trimethobenzamide in clinical trials, nausea and vomiting were reported in 31 and 11%, respectively, of patients treated with apomorphine subcutaneous injection (Apokyn^®).1 In a clinical study of the subcutaneous infusion formulation (Onapgo^®), 87% of patients were pretreated with an antiemetic; 22% reported nausea and 7% reported vomiting (compared to 9% and 4%, respectively, with placebo).2 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.1,  2

Concomitant use of apomorphine with antiemetics that inhibit dopamine receptors should be avoided.1,  2 Carefully consider risks and benefits of such concomitant use.1,  2

Falling Asleep During Activities of Daily Living and Somnolence

Patients receiving apomorphine have reported falling asleep while engaged in activities of daily living.1,  2 Although somnolence is commonly associated with apomorphine, these patients perceived no warning signs and believed they were alert immediately prior to the event.1,  2

Falling asleep while engaged in activities of daily living is thought to always occur in a setting of preexisting somnolence although patients may not give such a history.1,  2 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,  2 Clinicians also should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1,  2

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,  2 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,  2 If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities.1,  2 There is insufficient information to establish whether dosage reduction will eliminate this adverse effect.1,  2

Syncope/Hypotension/Orthostatic Hypotension

Dopamine agonists appear to impair systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dosage escalation.1,  2 Patients with Parkinson disease may also have an impaired capacity to respond to an orthostatic challenge.1,  2 Apomorphine causes dose-related decreases in systolic and diastolic blood pressure.1

Orthostatic hypotension, hypotension, and/or syncope were reported in approximately 11% of patients receiving apomorphine subcutaneous injection (Apokyn^®) in clinical studies; these adverse effects were observed during initiation of apomorphine therapy as well as during long-term treatment.1 In the clinical study of apomorphine subcutaneous infusion (Onapgo^®), orthostatic hypotension or hypotension was reported in 13 or 2% of patients who received the drug or placebo.2

Patients receiving apomorphine should be monitored for signs and symptoms of orthostatic hypotension, particularly during dosage escalation, and should be informed of this risk.1,  2 Because of additive hypotensive effects, concomitant use of alcohol is not recommended.1,  2

Patients taking apomorphine should lie down before and after taking sublingual nitroglycerin.1,  2 Patients taking other vasodilators or antihypertensive agents should be monitored closely for hypotension and orthostatic hypotension during concomitant use of apomorphine.1,  2

Falls

Patients with Parkinson disease are at risk of falling as a result of underlying postural instability and autonomic instability.1,  2 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,  2 In clinical trials of apomorphine subcutaneous injection (Apokyn^®), 30% of patients had events that could be considered falls and about 5% of patients had falls that were considered serious.1

Infusion Site Reactions and Infections

The formulation of apomorphine administered by subcutaneous infusion (Onapgo^®) can cause infusion site reactions (e.g., nodules, erythema, hematomas, inflammation, pruritus, swelling, discoloration, hemorrhage, hypersensitivity, induration, edema, pain, rash, and bruising) and infections.2 In the clinical study evaluating this preparation, infusion site reactions were reported in 63% of patients treated with the drug and infusion site infections were reported in 4% of patients.2 Cellulitis was the most frequently reported infusion site infection.2 If an infection is suspected at the infusion site, remove the cannula from the infusion site.2 If the cannula is removed for an infection, place a new cannula at a new infusion site.2 In the event of a prolonged interruption of apomorphine therapy, oral medications should be prescribed to treat the patient's Parkinson disease.2

Hallucinations/Psychotic-like Behavior

Hallucinations or psychotic-like behavior have been reported in patients receiving apomorphine in clinical studies.1,  2

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

The manufacturer of apomorphine (Apokyn^®) states that patients with a major psychotic disorder should ordinarily not be treated with the drug because of the risk of exacerbating psychosis.1 Consider the risks and benefits prior to initiating treatment with apomorphine in patients with a major psychotic disorder.2 In addition, consider that concomitant use with antipsychotic agents may exacerbate parkinsonian symptoms and decrease effectiveness of apomorphine.1,  2

Dyskinesia

Apomorphine may cause or exacerbate dyskinesias.1,  2 Dyskinesia or worsening of dyskinesia was reported in 24% of patients treated with apomorphine (Apokyn^®) and resulted in discontinuance of the drug in 2% of patients in clinical studies.1 In the clinical study of apomorphine (Onapgo^®), dyskinesia or worsening of dyskinesia was reported in approximately 15% of patients treated with the drug.2

Hemolytic Anemia

During postmarketing experience, hemolytic anemia requiring hospitalization has been reported with apomorphine.1,  2 Severe anemia, angina, and dyspnea have occurred with hemolytic anemia.1,  2 Several cases included positive direct antiglobulin test (Coombs test), suggesting a potential immune-mediated hemolysis.1,  2 Some patients were treated with high-dose glucocorticoids or blood transfusions.1,  2 Hemolytic anemia may occur at any time following apomorphine treatment.1,  2

If a patient develops anemia during treatment with apomorphine, consider a workup for hemolytic anemia.1,  2 If hemolytic anemia occurs, consider discontinuing apomorphine treatment.1,  2

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,  2 In some cases, urges stopped when dosage was reduced or the drug was discontinued.1,  2

Because patients may not recognize these behaviors as abnormal, clinicians should specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges during treatment with apomorphine.1,  2 Consider reducing dosage or discontinuing therapy if a patient develops such urges.1,  2

Cardiac Events

Cardiac events have been reported in patients receiving apomorphine.1,  2 Angina, myocardial infarction (MI), cardiac arrest, and/or sudden death were reported in 4% of patients receiving apomorphine subcutaneous injection (Apokyn^®) in clinical studies.1 Angina and MI occurred in some patients in close proximity to injection dosing (within 2 hours); cardiac arrest and sudden death occurred at times unrelated to dosing in some patients.1

In the clinical study of apomorphine subcutaneous infusion (Onapgo^®), 4 patients treated with the drug experienced cardiac disorders, including left bundle branch block, MI, palpitations, or tachycardia.2

Apomorphine may exacerbate coronary and cerebral ischemia as a result of its effect on blood pressure.1,  2 The drug should be used with extreme caution in patients with known cardiovascular and cerebrovascular disease.1,  2 If patients develop signs and symptoms of coronary or cerebral ischemia, the continued use of apomorphine should be carefully evaluated.1,  2

Prolongation of QT Interval and Potential for Proarrhythmic Effects

Apomorphine is associated with a risk of dose-related QT-interval prolongation after exposure similar to that achieved with therapeutic doses of the drug.1,  2 Although torsades de pointes has not been observed in association with apomorphine use at recommended doses in clinical studies, an increased risk cannot be ruled out.1,  2

The use of apomorphine (Apokyn^®) 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 QTc interval).1,  2

Withdrawal-emergent 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 lowering, or changes in antiparkinsonian therapy.1

Hypersensitivity

Hypersensitivity/allergic reactions (e.g., urticaria, rash, pruritus, angioedema) caused by apomorphine or the sulfite excipient have been reported.1,  2 The commercially available formulation of apomorphine hydrochloride injection contains sodium metabisulfite, which can cause serious allergic-type reactions in certain susceptible individuals.1,  2 The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.1,  2 Sulfite sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.1,  2

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,  2 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,  2

Priapism

Apomorphine may cause prolonged painful erections.1,  2 Severe priapism may require surgical intervention.1,  2

Retinal Pathology in Albino Rats

In a 2-year carcinogenicity study of apomorphine in albino rats, retinal atrophy was observed at all subcutaneous doses tested (less than the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area basis).1,  2 However, retinal degeneration was not observed in a 39-week study of apomorphine in monkeys given a dose similar to the MRHD on a body surface area basis.1,  2

Retinal degeneration has been observed in albino rats given other dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies).1,  2

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,  2

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of apomorphine in pregnant women.1,  2 In animal reproduction studies, an increased incidence of neonatal deaths and cardiovascular malformations was observed at clinically relevant doses associated with maternal toxicity.1,  2

Lactation

It is not known whether apomorphine is distributed into human milk; effects of the drug on the breast-fed infant or on milk production also are not known.1,  2 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,  2

Pediatric Use

Safety and efficacy of apomorphine have not been established in pediatric patients.1,  2

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 treated with intermittent subcutaneous apomorphine relative to younger adults.1 Clinical studies of apomorphine administered via continuous subcutaneous infusion did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger adults.2

Hepatic Impairment

Peak plasma concentrations and AUC were increased by 25 and 10%, respectively, in patients with mild to moderate hepatic impairment compared to healthy individuals; the drug should be used with caution in such patients.1,  2 Apomorphine has not been evaluated systematically in patients with severe hepatic impairment.1,  2

Renal Impairment

The initial dose of apomorphine hydrochloride should be reduced in patients with mild to moderate renal impairment; peak plasma concentrations and AUC were increased by 50 and 16%, respectively, in such patients.1,  2 Apomorphine has not been evaluated systematically in patients with severe renal impairment.1,  2

Common Adverse Effects

The most common adverse effects of apomorphine (Apokyn^®) (incidence ≥10% versus placebo) include yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities.1

The most common adverse effects of apomorphine (Onapgo^®) (incidence ≥10% on apomorphine and at least twice the rate of placebo) include infusion site nodule, nausea, somnolence, infusion site erythema, dyskinesia, headache, and insomnia.2

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; exercise caution if apomorphine is used concomitantly with QT-prolonging medications.1,  2

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions are unlikely.1,  2

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, granisetron, dolasetron, palonosetron, alosetron).1,  2 Concomitant use is contraindicated.1,  2

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,  2

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,  2

Hypotensive Agents and Vasodilators

Additive hypotensive effects may occur; caution is advised during concomitant use.1,  2

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

The hypotensive effects of apomorphine are increased with concurrent use of alcohol or sublingual nitroglycerin.1,  2 Concomitant use of apomorphine and alcohol should be avoided.1,  2 If nitroglycerin is used in a patient receiving apomorphine, the patient should be instructed to lie down before and after taking nitroglycerin.1,  2

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,  2

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,  2 Pharmacokinetic interaction is unlikely.1,  2

Catechol- O -Methyltransferase (COMT) Inhibitors

Pharmacokinetic interaction is unlikely; apomorphine does not appear to be metabolized by COMT.1,  2

Description

Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist that is structurally and pharmacologically related to dopamine.1,  2,  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,  2 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

Following a single subcutaneous injection, apomorphine exhibits linear pharmacokinetics over a dose range of 2-8 mg.1 Apomorphine is rapidly absorbed following subcutaneous administration in the abdominal wall; bioavailability following subcutaneous administration is equal to that of IV administration.1,  2 Following subcutaneous injection, peak concentrations are reached within 10-60 minutes; maximum concentrations in the CSF are <10% of the maximum plasma concentrations and occur within 10-20 minutes.1 Following initiation of a continuous subcutaneous infusion, steady-state concentrations are reached within approximately 2 hours.2 However, the time to reach 50% of infusion steady-state concentrations can be reduced by 50-75% by administering an extra dose when the continuous dose is initiated.2 If the extra dose is administered ≥2 hours after the initiation of a continuous dose, supplemental exposure from the extra dose reaches a maximum concentration within 20-40 minutes.2 Apomorphine is 89% protein-bound.2 The mean elimination half-life is 40 minutes.1,  2 Metabolism of apomorphine occurs primarily via conjugation.2 Within 30 minutes of administering a subcutaneous dose of radiolabeled apomorphine, only 8.3% of plasma radioactivity was apomorphine; 83% was apomorphine sulfate, 3.5% was apomorphine glucuronide, and 1% was nor-apomorphine glucuronide.2 Following a subcutaneously administered dose of radiolabeled apomorphine, 86% of the dose was recovered in the urine within 48 hours (as apomorphine sulfate, apomorphine glucuronide, and nor-apomorphine glucuronide) and 4.6% was recovered in the feces over 144 hours (as apomorphine sulfate, apomorphine glucuronide, and apomorphine).2 No clinically significant pharmacokinetic differences were observed based on age, gender, weight, duration of Parkinson disease, levodopa dose, or duration of therapy.1,  2

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.2
• Instruct patients and caregivers that Apokyn^® is dosed in milliliters, not milligrams.1
• If using the Apokyn^® pen, inform patients and caregivers that it is possible to dial in their usual dose of Apokyn^® even though the cartridge may contain less than that amount of drug.1 In this case, they will receive only a partial dose with the injection, and the amount left to inject will appear in the dosing window.1 To complete the correct dose, patients/caregivers will need to "re-arm" the device and dial in the correct amount of the remaining dose.1 Patients and caregivers should be alerted to the fact that there may be insufficient drug left in the cartridge to deliver a complete dose (for example, patients and caregivers should be urged to keep records of how many doses they have delivered for each cartridge, so that they can replace any cartridge that has an inadequate amount of drug remaining).1
• Advise patients using Onapgo^® that a new single-dose cartridge and cartridge holder and a new infusion line should be used each day.2
• Instruct patients to rotate the injection site and to observe proper aseptic technique.1,  2
• Advise patients that apomorphine is intended only for subcutaneous injection and must not be given IV because of the risk of serious complications such as thrombus formation and pulmonary embolism due to crystallization.1,  2
• Advise patients that hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of apomorphine or any of its excipients, including a sulfite (i.e., sodium metabisulfite).1,  2 Inform patients with a sulfite sensitivity that they may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks.1,  2 Advise patients who experience any hypersensitivity/allergic reaction to apomorphine that they should not take apomorphine again.1,  2
• Advise patients they may experience nausea and/or vomiting, which may be severe, and that treatment with oral trimethobenzamide 300 mg 3 times per day for 3 days prior to starting apomorphine injections has been used to help minimize these symptoms.1,  2 Alternatively, starting apomorphine at a lower dose and titrating based on individual tolerance and treatment effect may be attempted.1,  2 Advise patients that apomorphine taken with trimethobenzamide may increase the risks for somnolence, dizziness, and falls, and to consult their healthcare provider before discontinuing trimethobenzamide.1,  2
• Alert patients to the potential sedating effects of apomorphine, including somnolence and falling asleep while engaged in activities of daily living.1,  2 Instruct patients not to drive a car or engage in other potentially dangerous activities until they have gained sufficient experience with apomorphine to gauge whether or not it affects their mental and/or motor performance adversely.1,  2 Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) occur, they should not drive or participate in potentially dangerous activities until they have contacted their physician.1,  2 Because of possible additive effects of alcohol use, advise patients to limit their alcohol intake.1
• Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating.1,  2 Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after months of treatment).1,  2 Instruct patients to rise slowly after sitting or lying down while taking apomorphine.1,  2 Inform patients that alcohol and nitroglycerin (and possibly other vasodilators and antihypertensive medications) may potentiate the hypotensive effect of apomorphine.1,  2 Instruct patients ideally to lie down before taking sublingual nitroglycerin and to remain supine and avoid standing for at least 45 minutes after nitroglycerin.1,  2 Instruct patients of the increased hypotensive effects of apomorphine taken with nitroglycerin or by taking apomorphine after alcohol ingestion.1,  2
• Alert patients that they may have increased risk for falling when using apomorphine.1,  2
• Inform patients that injections of Apokyn^® may result in injection site reactions including bruising, granuloma, and pruritus.1 Inform patients that infusion of Onapgo^® may result in infusion site reactions, including, but not limited to nodules, erythema, bruising, and infection.2 Infusion site infections were reported in <5% of patients on Onapgo^® in clinical trials.2 Instruct patients to change the infusion site every day and to observe proper aseptic technique.2
• Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur.1,  2 Advise patients to inform their healthcare provider if they have a major psychotic disorder or are taking any treatments for psychosis.2 Tell patients if they have a major psychotic disorder, ordinarily they should not use Apokyn^® because of the risk of exacerbating the psychosis.1 Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of apomorphine.1,  2
• Inform patients that apomorphine may cause and/or exacerbate pre-existing dyskinesia.1,  2
• Inform patients and caregivers that hemolytic anemia may occur and to contact their healthcare provider if they develop any signs or symptoms.1,  2
• Patients and their caregivers should be alerted to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges, and the inability to control these urges while taking apomorphine.1,  2
• Inform patients that Apokyn^® may cause coronary events including angina and myocardial infarction and Onapgo^® may cause cardiac (and cerebral) ischemia and these outcomes could possibly be related to significant hypotension/orthostatic hypotension.1,  2
• Alert patients that apomorphine may cause QTc prolongation and might produce proarrhythmic effects that could cause torsades de pointes and sudden death.1,  2 Palpitations and syncope may signal the occurrence of an episode of torsades de pointes.1,  2
• Advise patients to contact their healthcare provider if they wish to discontinue or decrease the dose of Apokyn^®.1
• Advise patients that apomorphine may cause prolonged painful erections and that if this occurs, they should seek medical attention immediately.1,  2
• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,  2
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,  2
• Advise patients of other important precautionary information.1,  2

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. MDD US Operations, LLC. Apokyn^® (apomorphine hydrochloride) injection prescribing information. Rockville, MD; 2025 Jan.

2. MDD US Operations, LLC. Onapgo^® (apomorphine hydrochloride) injection prescribing information. Rockville, MD; 2025 Feb.

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

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. Search orphan drug designations and approvals. From FDA website. [Web]

8. Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH; APO302 Study Investigators. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson's disease. Parkinsonism Relat Disord. 2007;13(2):93-100.

21. 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(9):749-759.

22. Katzenschlager R, Poewe W, Rascol O, et al. Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study. Parkinsonism Relat Disord. 2021;83:79-85.

23. Pringsheim T, Day GS, Smith DB, et al. Dopaminergic Therapy for Motor Symptoms in Early Parkinson Disease Practice Guideline Summary: A Report of the AAN Guideline Subcommittee. Neurology. 2021;97(20):942-957.

24. Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease. Mov Disord. 2018;33(8):1248-1266.

400. Centers for Disease Control and Prevention National Institute for Occupational Safety and Health. NIOSH list of hazardous drugs in healthcare settings, 2024. From CDC website. Accessed 2025 Apr 29. [Web]