ONAPGO

Subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of ONAPGO. ( 5.1 ) May cause nausea and vomiting. ( 2.2 , 5.2 ) Falling asleep during activities of daily living and daytime somnolence may occur. ( 5.3 ) May cause hypotension/orthostatic hypotension and syncope may occur. ( 5.4 ) May cause or increase the risk of falls. ( 5.5 ) May cause infusion site reactions and infections. Monitor and change infusion site every day. ( 2.4 , 5.6 ) May cause hallucinations and psychotic-like behavior. ( 5.7 ) May cause dyskinesia or exacerbate pre-existing dyskinesia. ( 5.8 ) May cause hemolytic anemia. ( 5.9 ) May cause impulse control/ compulsive and impulsive behaviors. Consider dose reductions or stopping ONAPGO. ( 5.10 ) May cause cardiac events. ( 5.11 ) May prolong QTc and cause torsades de pointes or sudden death. ( 5.12 ) 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 3 antiemetics 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 2 basis. 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.