Can Apomorphine cause dyskinesia?

ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling: Serious Adverse Reactions After Intravenous Administration [see Warnings and Precautions (5.1) ] Nausea and Vomiting [see Warnings and Precautions (5.2) ] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3) ] Syncope/Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4) ] Falls [see Warnings and Precautions (5.5) ] Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.6) ] Dyskinesias [see Warnings and Precautions (5.7) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.8) ] Coronary Events [see Warnings and Precautions (5.9) ] QTc Prolongation and Potential for Proarrhythymic Effects [see Warnings and Precautions (5.10) ] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.11) ] Hypersensitivity [see Warnings and Precautions (5.12) ] Fibrotic Complications [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence at least 10% greater on apomorphine hydrocloride than on placebo) were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice. In placebo-controlled trials, most patients received only one subcutaneous dose of apomorphine hydrocloride. All patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients had some degree of spontaneously occurring periods of hypomobility ("off episodes") at baseline. The most common adverse reactions (apomorphine hydrocloride incidence at least 10% greater than placebo incidence) observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities. Table 1 presents the most common adverse reactions reported by apomorphine hydrocloride-naïve Parkinson's disease patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were treated for up to 4 weeks (Study 1) [see Clinical Studies (14) ] . Individual apomorphine hydrocloride doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms. Table 1: Adverse Reactions Occurring in Two or More Apomorphine Hydrocloride-Treated Patients in Study 1 Apomorphine Hydrocloride (n = 20) PLACEBO (n = 9) % % Yawning 40 0 Dyskinesias 35 11 Drowsiness or Somnolence 35 0 Nausea and/or Vomiting 30 11 Dizziness or Postural Hypotension 20 0 Rhinorrhea 20 0 Chest Pain/Pressure/Angina 15 11 Hallucination or Confusion 10 0 Edema/Swelling of Extremities 10 0 Other Adverse Reactions Injection Site Reactions Patients treated with apomorphine hydrocloride subcutaneous injections during clinical studies, 26% of patients had injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). In addition to those in Table 1, the most common adverse reactions in pooled apomorphine hydrocloride trials (occurring in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, Parkinson's disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.

WARNINGS AND PRECAUTIONS For subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of apomorphine hydrocloride ( 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 problems with impulse control and impulsive behaviors ( 5.8 ) May cause coronary events ( 5.9 ) May prolong QTc and cause torsades de pointes or sudden death ( 5.10 ) 5.1 Serious Adverse Reactions After Intravenous Administration Following intravenous administration of apomorphine hydrocloride, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, apomorphine hydrocloride should not be administered intravenously. 5.2 Nausea and Vomiting Apomorphine hydrocloride causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated 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 apomorphine hydrocloride-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued apomorphine hydrocloride due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine hydrocloride. 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 apomorphine hydrocloride 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 apomorphine hydrocloride 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 apomorphine hydrocloride subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with apomorphine hydrocloride, 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 apomorphine hydrocloride 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 apomorphine hydrocloride, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with apomorphine hydrocloride, 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.), apomorphine hydrocloride should ordinarily be discontinued. If a decision is made to continue apomorphine hydrocloride, 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 apomorphine hydrochloride-treated patients experienced syncope. Dopamine agonists, including apomorphine hydrochloride, 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 apomorphine hydrochloride showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (≥ 20 mmHg 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 mmHg) after subcutaneous apomorphine injection. In clinical trials of apomorphine hydrochloride 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 apomorphine hydrochloride 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. Apomorphine hydrochloride 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 apomorphine hydrochloride 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 apomorphine hydrochloride [see Drug Interactions ( 7.3 )]. Patients taking apomorphine hydrochloride should lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensives may also increase the hypotensive effects of apomorphine hydrochloride. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking apomorphine hydrochloride 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 apomorphine hydrocloride might increase the risk of falling by simultaneously lowering blood pressure an