Onapgo: Package Insert / Prescribing Info

2.1 Important Information

• ONAPGO is indicated for subcutaneous use by infusion only [see Warnings & Precautions (5.1)] .
• Patients selected for treatment with ONAPGO should be capable of understanding and trained on using the delivery system, either themselves or with the assistance of a caregiver [see Healthcare Provider Instructions for Use and Patient Instructions for Use].
• ONAPGO initiation and dose titrations should be done under medical supervision.
• The prescribed dose of ONAPGO should be expressed in "mg/hr" for the continuous dosage and "mg" for an extra dose.

2.2 Premedication and Concomitant Medication

Because of the incidence of nausea and vomiting with ONAPGO, it is recommended that treatment with trimethobenzamide 300 mg three times a day start 3 days prior to the initial dose of ONAPGO [see Adverse Reactions (6.1)and Warnings and Precautions (5.2)] . Alternatively, consider starting ONAPGO therapy, without antiemetics, at 1 mg/hour and titrate based upon effectiveness and tolerance.

If trimethobenzamide is used, it should be continued only as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with ONAPGO, as trimethobenzamide increases the incidence of somnolence, dizziness, and falls in patients treated with ONAPGO [see Warnings and Precautions (5.2)] .

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT 3antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated [see Contraindications (4)] .

After starting ONAPGO, adjustment of concomitant anti-Parkinson's disease medications may be necessary.

2.3 Recommended Dosage

ONAPGO (apomorphine hydrochloride) is administered as a subcutaneous infusion with the ONAPGO pump [see Dosage and Administration (2.3), Healthcare Provider Instructions for Use, and Patient Instructions for Use].

The daily dosage is determined by individualized patient titration and is composed of a continuous dosage and as needed extra dose(s).

The maximum recommended total daily dosage of ONAPGO, including the continuous dosage and any extra dose(s), is 98 mg per day, generally administered over the waking day (e.g., 16 hours).

2.4 Preparation and Administration Instructions

Patients and caregivers should receive education and be trained on the proper use of ONAPGO and the device delivery system prior to first use [see Dosage and Administration (2.2)and Patient Instructions for Use].

• Visually inspect solution for particulate matter and discoloration prior to administration. Solution should be clear, almost colorless. Do not use if solution is discolored or contains particles.
• Keep the infusion site clean and use aseptic technique.
• Administer ONAPGO subcutaneously in one of the following areas:
  • Abdomen at least 2 inches away from the navel
  • Top of thigh
  • Lower back
  • Upper back, only when the infusion site is being prepared by a caregiver or healthcare provider
• Change the infusion site every day
• Do notselect an infusion site that is bruised, has bumps or nodules, or is irritated.
• A new single-dose cartridge and cartridge holder should be used each day. Discard unused portion.

2.5 Recommended Dosage in Patients with Renal Impairment

For patients with mild or moderate renal impairment, the recommended initial extra dose is 0.5 mg to 1 mg and should not exceed 1 mg [see Clinical Pharmacology (12.3)and Use in Specific Populations (8.6)]. No adjustment is needed for the continuous dose, maximum recommended daily dose, or subsequent extra doses after the initial extra dose [see Dosage and Administration (2.3)]. Patients with severe renal impairment have not been studied.

2.6 Discontinuation of ONAPGO

Sudden discontinuation or rapid dose reduction of ONAPGO could result in increased severity of Parkinson's disease motor symptoms. If possible, ONAPGO should be tapered before discontinuing.

5.1 Serious Adverse Reactions After Intravenous Administration

Following intravenous administration of apomorphine, serious adverse reactions including thrombus formation and pulmonary embolism caused by intravenous crystallization of apomorphine have occurred. Do not administer ONAPGO intravenously.

5.2 Nausea and Vomiting

ONAPGO is known to cause nausea and vomiting, which may be severe. In Study 1 [see Clinical Studies (14)] 87% of patients were pretreated with an antiemetic. Twenty-two percent of patients treated with ONAPGO reported nausea and 7% reported vomiting, compared to 9% and 4%, respectively, of patients who received placebo. The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) to reduce apomorphine-associated nausea/vomiting has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide) have the potential to worsen the symptoms in patients with PD and therefore the benefits and risks of treatment with these antiemetics should be carefully considered. The use of ONAPGO with 5HT 3antiemetics is contraindicated.

5.3 Falling Asleep During Activities of Daily Living and Somnolence

Somnolence is commonly associated with ONAPGO .Patients treated with dopaminergic medications, including apomorphine, have also reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In the double-blind placebo-controlled trial (Study 1), somnolence was reported in 22% of patients treated with ONAPGO and 4% of patients in the placebo group.

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although patients may not give such a history. Therefore, prescribers should reassess patients for drowsiness or sleepiness while using ONAPGO, especially because some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with ONAPGO, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with ONAPGO, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.), ONAPGO should ordinarily be discontinued. If a decision is made to continue ONAPGO, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.4 Syncope/Hypotension/Orthostatic Hypotension

Dopamine agonists, including ONAPGO, may cause orthostatic hypotension at any time, but especially during dose escalation. Patients with PD may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, PD patients being treated with dopaminergic agonists should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

When evaluated at various times after dosing in Study 1, patients undergoing titration of ONAPGO showed an increased incidence (from 4.5% pre-dose to 44.4% post-dose) of systolic orthostatic hypotension (≥ 20 mm Hg decrease upon standing) compared to placebo (7.1% pre-dose to 16.3% post-dose). Similarly, increased incidences of diastolic orthostatic hypotension (≥ 10 mm Hg decrease upon standing) were noted in patients titrated with ONAPGO (4.5% pre-dose to 44.4% post-dose) compared to placebo (11.9% pre-dose to 30.2% post-dose). Through the 12-week treatment period, these differences in incidence rates for systolic and diastolic orthostatic hypotension remained similar between ONAPGO and placebo patients. Patients in both ONAPGO and placebo groups developed severe systolic orthostatic hypotension (≥ 40 mm Hg decrease) and/or diastolic orthostatic hypotension (≥ 20 mm Hg decrease).

In Study 1, 13% of patients treated with ONAPGO reported hypotension or orthostatic hypotension compared to 2% of patients who received placebo [hypotension (7% vs 0%), orthostatic hypotension (4% vs 2%), and orthostatic intolerance (2% vs 0%)]. In the double-blind period of Study 1, one patient (2%) experienced a serious adverse event of hypotension and withdrew from the study compared to none in placebo.

Syncope has been reported in patients who have received subcutaneous apomorphine.

Patients with PD may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, PD patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. Patients should avoid alcohol when using ONAPGO [see Drug Interactions (7.3)] . Patients taking ONAPGO should lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensives may also increase the hypotensive effects of ONAPGO. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking ONAPGO with concomitant antihypertensive medications or vasodilators [see Drug Interactions (7.2)].

5.5 Falls

Patients with Parkinson's disease are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat Parkinson's disease. ONAPGO might increase the risk of falling by simultaneously lowering blood pressure and altering mobility [see Warnings and Precautions (5.4)and Clinical Pharmacology (12.2)]. Falls, including serious falls, have been reported in patients treated with apomorphine.

5.6 Infusion Site Reactions and Infections

ONAPGO can cause infusion site reactions and infections.

In Study 1, one or more infusion site reactions were reported in 63% of patients treated with ONAPGO and 15% in patients who received placebo. Various types of reactions at the infusion site have been reported including nodules, erythema, hematomas, inflammation, pruritus, swelling, discoloration, hemorrhage, hypersensitivity, induration, edema, pain, rash, or bruising [see Adverse Reactions (6.1)] . In Study 1, 2% of patients treated with ONAPGO and no patient who received placebo discontinued treatment because of an infusion site reaction.

Infusion site infections occurred in 4% of patients treated with ONAPGO compared to no patients who received placebo. The most frequent infusion site infection reported was cellulitis. If an infection is suspected at the infusion site, the cannula should be removed from the infusion site. If the cannula is removed for an infection, a new cannula should be placed at a new infusion site. In the event of a prolonged interruption of treatment with ONAPGO, the patient should be prescribed oral medications to treat their Parkinson's disease [see Dosage and Administration (2.4)].

5.7 Hallucinations/Psychotic-Like Behavior

In Study 1, 4% of patients treated with ONAPGO reported hallucinations compared to 4% of patients who received placebo. Psychotic disorder was reported in 2% of patients treated with ONAPGO compared to none who received placebo.

Postmarketing reports with intermittent subcutaneous apomorphine indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of apomorphine. Other drugs prescribed to improve the symptoms of PD can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Consider the risks and benefits prior to initiating treatment with ONAPGO in patients with a major psychotic disorder because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of PD and may decrease the effectiveness of ONAPGO [see Drug Interactions (7.3)] .

5.8 Dyskinesia

ONAPGO may cause dyskinesia or exacerbate pre-existing dyskinesia. In Study 1, dyskinesia or worsening of dyskinesia was reported in approximately 15% of patients treated with ONAPGO compared to no patients who received placebo.

5.9 Hemolytic Anemia

Hemolytic anemia requiring hospitalization has been reported with apomorphine treatment in a postmarketing setting. Many of the reported cases included positive direct antiglobulin test (Coombs test), suggesting a potential immune-mediated hemolysis. Severe anemia, angina, and dyspnea have occurred with hemolytic anemia. Some patients were treated with high dose glucocorticoids or blood transfusions. Hemolytic anemia can occur at any time after apomorphine treatment. If a patient develops anemia while taking ONAPGO, consider a workup for hemolytic anemia. If hemolytic anemia occurs, consider discontinuing treatment with ONAPGO. In Study 1, hemolytic anemia was reported in 2% of patients treated with ONAPGO compared to no patient who received placebo.

5.10 Impulse Control/Compulsive Behaviors

Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking one or more of the medications, including ONAPGO, that increase central dopaminergic tone and that are generally used for the treatment of PD. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with ONAPGO. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ONAPGO

5.11 Cardiac Events

In Study 1, 4 patients treated with ONAPGO experienced cardiac disorders, including left bundle branch block (2%), myocardial infarction (2%), palpitations (2%), or tachycardia (2%), compared to no patients who received placebo. In patients treated with apomorphine subcutaneous injection, cardiac arrest and/or sudden death has occurred; some cases of angina and myocardial infarction occurred in close proximity to apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing.

ONAPGO has been shown to reduce resting systolic and diastolic blood pressure and may have the potential to exacerbate cardiac (and cerebral) ischemia in patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of cardiac or cerebral ischemia, prescribers should re-evaluate the continued use of ONAPGO.

5.12 QTc Prolongation and Potential for Proarrhythmic Effects

There is a dose-related prolongation of QTc interval after apomorphine exposure similar to that achieved with therapeutic doses of ONAPGO [see Clinical Pharmacology (12.2)] . In Study 1, 4% of patients treated with ONAPGO experienced prolonged QTc interval compared to none who received placebo.

Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of ONAPGO at recommended doses in clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes.

The risks and benefits of ONAPGO treatment should be considered prior to initiating treatment with ONAPGO in patients with risk factors for prolonged QTc.

5.13 Hypersensitivity

In Study 1, 11% of patients treated with ONAPGO reported rash (4%), infusion site pruritus (4%), infusion site rash (2%), hypersensitivity (2%), or infusion site hypersensitivity (2%) compared to no patient who received placebo. Hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of ONAPGO or because of its sulfite excipient. ONAPGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

5.14 Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, whether other, non-ergot-derived dopamine agonists, such as ONAPGO, can cause these reactions is unknown.

5.15 Priapism

In clinical studies of intermittent apomorphine injection, painful erections were reported in 3 of 361 men treated with subcutaneous injection, and one patient withdrew from therapy because of priapism. Although no patients in the clinical studies required surgical intervention, severe priapism may require surgical intervention.

5.16 Retinal Pathology in Albino Rats

In a two-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less than the maximum recommended human dose (MRHD) of 98 mg/day on a body surface area [mg/m 2] basis). Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for prolonged periods (generally during two-year carcinogenicity studies). Retinal findings were not observed in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a dose similar to the MRHD on a mg/m 2basis. The clinical significance of the finding in rat has not been established but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 197 Parkinson's disease patients were exposed to ONAPGO in Study 1 and subsequent open-label studies.

In Study 1 [see Clinical Studies (14)], the most common adverse reactions (incidence 10% or greater in patients treated with ONAPGO and at a rate at least twice the placebo rate) were infusion site nodule, nausea, somnolence, infusion site erythema, dyskinesia, headache, and insomnia.

Table 1 presents adverse reactions that occurred in ≥5% of patients treated with ONAPGO and that occurred more frequently than placebo in patients who were enrolled in Study 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of apomorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematologic and Lymphatic Systems: hemolytic anemia [see Warnings and Precautions (5.9)]

7.1 5HT 3Antagonists

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of ONAPGO with 5HT 3antagonists, including antiemetics (e.g., ondansetron, granisetron, palonosetron) and alosetron, is contraindicated [see Warnings and Precautions (5.4)].

7.2 Antihypertensive Medications and Vasodilators

In clinical studies with intermittent subcutaneous administration of apomorphine, the following adverse reactions were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n=94) than in patients not receiving these medications (n=456): hypotension (10% vs 4%) myocardial infarction (3% vs 1%), [see Warnings and Precautions (5.4, 5.11)].

In a study of healthy subjects, concomitant administration of 0.4 mg sublingual nitroglycerin with subcutaneous apomorphine caused greater decreases in blood pressure than with subcutaneous apomorphine alone [see Clinical Pharmacology (12.3)]. Patients treated with ONAPGO should lie down before and after taking sublingual nitroglycerin to decrease the potential risks associated with hypotension .

7.3 Alcohol

In a study of healthy subjects, concomitant administration of high dose (0.6 g/kg) or low dose (0.3 g/kg) ethanol with apomorphine caused greater decreases in blood pressure than with apomorphine alone [see Clinical Pharmacology (12.3)] . Patients should be advised not to consume alcohol while treated with ONAPGO because it may cause greater decreases in blood pressure [see Warnings and Precautions (5.4)] .

7.4 Dopamine Antagonists

Because ONAPGO is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of ONAPGO. Antiemetics with anti-dopaminergic actions should be avoided [see Warnings and Precautions (5.2)]. Patients with major psychotic disorders, treated with neuroleptics, should be treated with dopamine agonists only if the potential benefits outweigh the risks [see Warnings and Precautions (5.7)].

7.5 Drugs Prolonging the QT/QTc Interval

Caution should be exercised when prescribing ONAPGO concomitantly with drugs that prolong the QT/QTc interval [see Warnings and Precautions (5.12)and Clinical Pharmacology (12.2)] .

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbid disease or other drug therapy.

Clinical studies of ONAPGO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience with intermittent subcutaneous use of apomorphine has shown that the following adverse reactions were reported more frequently in patients 65 years of age or older (n=311) compared to patients less than 65 years of age (n=239): confusion; hallucinations; serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability); falls (experiencing bone and joint injuries); cardiovascular events; respiratory disorders; gastrointestinal events; and discontinuation of treatment as a result of one or more adverse reactions.

8.6 Renal Impairment

The initial extra dose of ONAPGO should not exceed 1 mg in patients with mild or moderate renal impairment because of increased apomorphine concentration and exposure (C maxand AUC) in these patients. Studies in patients with severe renal impairment have not been conducted [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Exercise caution and closely monitor if ONAPGO is administered to patients with mild or moderate hepatic impairment because of increased apomorphine concentration and exposure (C maxand AUC) in these patients. Studies in patients with severe hepatic impairment have not been conducted [see Clinical Pharmacology (12.3)] .

9.1 Controlled Substance

ONAPGO contains apomorphine, which is not a controlled substance.

9.2 Abuse

In premarketing clinical experience, apomorphine did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. However, there are rare postmarketing reports of abuse of medications containing apomorphine. In general, these reports consist of patients taking increasing doses of medication in order to achieve a euphoric state. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

12.1 Mechanism of Action

ONAPGO is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors. The precise mechanism of action of ONAPGO as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors within the caudate-putamen in the brain.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

ONAPGO injection is supplied as one carton (NDC 27505-006-05) that contains five single-dose prefilled glass cartridges, each containing 98 mg/20 mL (4.9 mg/mL) apomorphine hydrochloride as a clear, almost colorless solution.

The ONAPGO Pump Kit, ONAPGO Cartridge Holders, and appropriate infusion sets are supplied separately.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Administration Information

Refer patients to the Instructions for Use for complete administration instructions. Inform patients of aseptic technique and of subcutaneous administration site selection and rotation [see Dosage and Administration (2.4)].

Advise patients that a new single-dose cartridge and cartridge holder and a new infusion line should be used each day.

Advise patients that ONAPGO is intended only for subcutaneous use and must not be given intravenously because of the risk of serious complications, such as thrombus formation and pulmonary embolism due to crystallization [see Warnings and Precautions (5.1)] .

Hypersensitivity/Allergic Reactions

Advise patients that hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of ONAPGO or any of its excipients, including a sulfite (i.e., sodium metabisulfite). Inform patients with a sulfite sensitivity that they may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks [see Warnings and Precautions (5.13)] . Advise patients who experience any hypersensitivity/allergic reaction to ONAPGO that they should not take ONAPGO again [see Contraindications (4)].

Nausea and Vomiting

Advise patients that they may experience nausea and vomiting, which may be severe. Advise patients that their ONAPGO dosage may be adjusted to start at 1mg/hr, and titration can be based upon effectiveness and tolerability. Treatment with an antiemetic that is a non-5HT3 antagonist may be used if needed. Oral trimethobenzamide 300 mg 3 times per day for 3 days prior to starting ONAPGO infusion has been used in clinical studies to help lessen these symptoms. Advise patients that ONAPGO taken with trimethobenzamide may increase the risk for somnolence, dizziness, and falls, and to consult their healthcare provider before discontinuing trimethobenzamide [see Warnings and Precautions (5.2)].

Falling Asleep Suddenly and Sedation/Sleepiness

Alert patients to the potential sedating effects of ONAPGO, including somnolence and falling asleep while engaged in activities of daily living. Instruct patients not to drive a car or engage in other potentially dangerous activities until they have gained sufficient experience with ONAPGO to gauge whether or not it affects their mental and/or motor performance adversely. 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 [see Warnings and Precautions (5.3)].

Hypotension/Orthostatic Hypotension

Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. 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). Instruct patients to rise slowly after sitting or lying down while using ONAPGO. Inform patients that alcohol and nitroglycerin (and possibly other vasodilators and antihypertensive medications) may worsen the potential effects of hypotension caused by ONAPGO [see Warnings and Precautions (5.4)]. Instruct patients ideally to lie down before taking sublingual nitroglycerin and to remain supine and avoid standing for at least 45 minutes after nitroglycerin. Instruct patients to avoid alcohol while using ONAPGO.

Falls

Alert patients that they may have increased risk for falling when using ONAPGO [see Warnings and Precautions (5.5)].

Infusion Site Reactions and Infections

Inform patients that infusion of ONAPGO may result in infusion site reactions, including, but not limited to nodules, erythema, bruising, and infection. Infusion site infections were reported in <5% of patients on ONAPGO in clinical trials [see Warnings and Precautions (5.6)and Adverse Reactions (6.1)] . Instruct patients to change the infusion site every day and to observe proper aseptic technique [see Dosage and Administration (2.4)and Instructions for Use] .

Hallucinations and/or Psychotic-Like Behavior

Inform patients that ONAPGO may cause hallucinations or other manifestations of psychotic-like behavior. Advise patients to inform their healthcare provider if they have a major psychotic disorder or are taking any treatments for psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of ONAPGO [see Warnings and Precautions (5.7)] .

Dyskinesia

Inform patients that ONAPGO may cause and/or exacerbate pre-existing dyskinesia [see Warnings and Precautions (5.8)].

Hemolytic Anemia

Inform patients and caregivers that hemolytic anemia may occur and to contact their healthcare provider if they develop any signs or symptoms [see Warnings and Precautions (5.9)] .

Impulse Control / Compulsive Behaviors

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 using ONAPGO [see Warnings and Precautions (5.10)].

Cardiac Events

Inform patients that ONAPGO may cause cardiac (and cerebral) ischemia, and these outcomes could possibly be related to significant hypotension/orthostatic hypotension [see Warnings and Precautions (5.11)].

QTc Prolongation and Potential for Proarrhythmic Effects

Alert patients that ONAPGO may cause QTc prolongation and might produce proarrhythmic effects that could cause torsades de pointes and sudden death. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes [see Warnings and Precautions (5.12)].

Priapism

Advise patients that ONAPGO may cause prolonged painful erections and that if this occurs, they should seek medical attention immediately [see Warnings and Precautions (5.15)]