warnings and cautions
5 WARNINGS AND PRECAUTIONS For subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of APOKYN ( 5.1 ) Falling asleep during activities of daily living, and daytime somnolence may occur ( 5.3 ) Syncope and hypotension/orthostatic hypotension may occur ( 5.4 ) Falls may occur, or increase ( 5.5 ) May cause hallucinations and psychotic-like behavior ( 5.6 ) May cause dyskinesia or exacerbate pre-existing dyskinesia ( 5.7 ) May cause hemolytic anemia ( 5.8 ) May cause problems with impulse control and impulsive behaviors ( 5.9 ) May cause coronary events ( 5.10 ) May prolong QTc and cause torsades de pointes or sudden death ( 5.11 ) 5.1 Serious Adverse Reactions After Intravenous Administration Following intravenous administration of APOKYN, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, APOKYN should not be administered intravenously. 5.2 Nausea and Vomiting Nausea and vomiting, which may be severe, can happen with APOKYN when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were premedicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the APOKYN-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued APOKYN due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing APOKYN. The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years). The effect of trimethobenzamide on reducing nausea and vomiting during treatment with APOKYN was evaluated in a 12-week, placebo-controlled study in 194 patients. The study suggests that trimethobenzamide reduces the incidence of nausea and vomiting during the first 4 weeks of APOKYN treatment (incidence of nausea and vomiting 43% on trimethobenzamide vs. 59% on placebo). However, over the 12-week period, compared with placebo, patients treated with trimethobenzamide had a greater incidence of somnolence (19% for trimethobenzamide vs. 12% for placebo), dizziness (14% for trimethobenzamide vs. 8% for placebo), and falls (8% for trimethobenzamide vs. 1% for placebo). Therefore, the benefit of treatment with trimethobenzamide must be balanced with the risk for those adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months. The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided. 5.3 Falling Asleep During Activities of Daily Living and Somnolence There have been reports in the literature of patients treated with APOKYN subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with APOKYN, and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Somnolence was reported in 35% of patients treated with APOKYN and in none of the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, especially since 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 APOKYN, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with APOKYN, 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.), APOKYN should ordinarily be discontinued. If a decision is made to continue APOKYN, 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 In clinical studies, approximately 2% of APOKYN-treated patients experienced syncope. Dopamine agonists, including APOKYN, may cause orthostatic hypotension at any time but especially during dose escalation. Patients with Parkinson's disease may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease 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 undergoing titration of APOKYN showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (≥ 20 mm Hg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension (≥ 30 mm Hg decrease and systolic BP ≤ 90 mm Hg) after subcutaneous apomorphine injection. In clinical trials of APOKYN in patients with advanced Parkinson's disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (< 1%) and resulted in withdrawal of APOKYN in 10 patients (2%). These events occurred both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other significant adverse events seen (e.g., falls), is unknown. APOKYN causes dose-related decreases in systolic (SBP) and diastolic blood pressure (DBP) [see Clinical Pharmacology (12.2) ] . In a study of healthy subjects, the hypotensive effect of APOKYN on systolic and diastolic blood pressure was exacerbated by the concomitant use of alcohol or sublingual nitroglycerin (0.4 mg). Patients should avoid alcohol when using APOKYN [see Drug Interactions (7.3) ] . Patients taking APOKYN should lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensives may also increase the hypotensive effects of APOKYN. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking APOKYN with concomitant antihypertensive medications or vasodilators [see Drug Interactions (7.2 , 7.3) ]. 5.5 Falls Patients with Parkinson's disease (PD) 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 PD. Subcutaneous APOKYN might increase the risk of falling by simultaneously lowering blood pressure and altering mobility [see Clinical Pharmacology (12.2) ] . In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of patients had falls that were considered serious. 5.6 Hallucinations / Psychotic-Like Behavior In clinical studies, hallucinations were reported by 14% of the APOKYN-treated patients. In one randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of patients treated with APOKYN and 0% of patients treated with placebo. Hallucinations resulted in discontinuation of APOKYN in 1% of patients. Postmarketing reports 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 APOKYN. Other drugs prescribed to improve the symptoms of Parkinson's disease 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. Patients with a major psychotic disorder should ordinarily not be treated with APOKYN because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of APOKYN [see Drug Interactions (7.3) ] . 5.7 Dyskinesias APOKYN may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or worsening of dyskinesia was reported in 24% of patients. Overall, 2% of APOKYN-treated patients withdrew from studies due to dyskinesias. 5.8 Hemolytic Anemia Hemolytic anemia requiring hospitalization has been reported with apomorphine treatment in the 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 appear at any time after apomorphine treatment. If a patient develops anemia while taking APOKYN, consider a workup for hemolytic anemia. If hemolytic anemia occurs, consider discontinuing APOKYN treatment. 5.9 Impulse Control/Compulsive Behaviors Case reports suggest that patients can 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 APOKYN, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. 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 APOKYN. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking APOKYN. 5.10 Coronary Events In clinical studies, 4% of patients treated with APOKYN experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to APOKYN dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. APOKYN has been shown to reduce resting systolic and diastolic blood pressure and may have the potential to exacerbate coronary and cerebral ischemia in patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of APOKYN. 5.11 QTc Prolongation and Potential for Proarrhythymic Effects There is a dose related prolongation of QTc interval after apomorphine exposure similar to that achieved with therapeutic doses of APOKYN [see Clinical Pharmacology (12.2) ] . Doses greater than 6 mg do not provide additional clinical benefit and are not recommended. 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 APOKYN 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 APOKYN treatment should be considered prior to initiating treatment with APOKYN in patients with risk factors for prolonged QTc. 5.12 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. 5.13 Hypersensitivity Hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of APOKYN or because of its sulfite excipient. APOKYN 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, nonergot derived dopamine agonists, such as APOKYN, can cause these reactions is unknown. 5.15 Priapism APOKYN may cause prolonged painful erections in some patients. In clinical studies, painful erections were reported by 3 of 361 APOKYN-treated men, and one patient withdrew from APOKYN 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 2-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 of 20 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 2-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.