Apomorphine Hydrochloride

Apomorphine hydrochloride injection is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) in patients with advanced Parkinson's disease. Apomorphine hydrocloride inejction has been studied as an adjunct to other medications [see Clinical Studies (14) ] . Apomorphine hydrocloride injection is a non-ergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced Parkinson's disease ( 1 )

Apomorphine hydrocloride 30 mg/3 mL (10 mg/mL) containing apomorphine hydrochloride (as apomorphine hydrochloride hemihydrate), USP is supplied as a clear, colorless, sterile, solution in a 3 mL (30 mg) cartridge. The 3 mL (30 mg) glass cartridge for single-patient-use is used with a manual reusable pen injector (APOKYN ® Pen) which is supplied separately by a different manufacturer. A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 0.02 mL (0.2 mg) increments. The APOKYN ® pen injector is provided in a package with six needles. Injection; 30 mg/3 mL (10 mg/mL) as a clear, colorless, sterile solution available in single-patient-use cartridges ( 3 , 16 )

Apomorphine hydrocloride is contraindicated in patients: Using concomitant drugs of the 5HT 3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1) ] . There have been reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron. With hypersensitivity/allergic reaction to apomorphine or to any of the excipients of apomorphine hydrocloride, including a sulfite (i.e., sodium metabisulfite). Angioedema or anaphylaxis may occur [see Warnings and Precautions (5.12) ]. Concomitant use of apomorphine hydrocloride with 5HT 3 antagonists, including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated ( 4 ) Hypersensitivity to apomorphine, its excipients or sodium metabisulfite ( 4 , 5.12 )

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. […]

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.

Concomitant use of antihypertensive medications and vasodilators: increased risk for hypotension, myocardial infarction, pneumonia, falls, and injuries ( 7.2 ) Dopamine antagonists such as neuroleptics or metoclopramide, may diminish the effectiveness of apomorphine hydrocloride ( 7.4 ) 7.1 5HT 3 Antagonists Based on reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron, the concomitant use of apomorphine hydrocloride with 5HT 3 antagonists including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated.

7.2 Antihypertensive Medications and Vasodilators In clinical studies, the following adverse events 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%) [see Warnings and Precautions (5.4) ] , myocardial infarction (3% vs 1%), serious pneumonia (5% vs 3%), serious falls (9% vs 3%), and bone and joint injuries (6% vs 2%). Some of the events may be related to the increased incidence of hypotension in patients receiving concomitant antihypertensive medications or vasodilators [see Warnings and Precautions (5.4 , 5.5) ] . Concomitant administration of 0.4 mg sublingual nitroglycerin with apomorphine hydrocloride in healthy subjects causes greater decreases in blood pressure compared to apomorphine hydrocloride alone. When nitroglycerin and apomorphine hydrocloride were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject's largest drop in blood pressure measured within the 6-hour period following administration of apomorphine hydrocloride) in supine systolic and diastolic blood pressure (measured over 6 hours) was 9.7 mm Hg and 9.3 mm Hg, respectively [see Clinical Pharmacology (12.3) ]. The mean largest decrease in standing systolic and diastolic blood pressure was 14.3 mm Hg and 13.5 mm Hg, respectively. Some individuals experienced very large decreases in standing systolic and diastolic blood pressure, up to a maximum decrease of 65 mm Hg and 43 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when apomorphine hydrocloride was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg and 8.4 mm Hg, respectively. Patients taking apomorphine hydrocloride should lie down before and after taking sublingual nitroglycerin [see Warnings and Precautions (5.4) ].

7.3 Alcohol Concomitant administration of high dose (0.6 g/kg) or low dose (0.3 g/kg) ethanol with apomorphine hydrocloride in healthy subjects causes greater decreases in blood pressure compared to apomorphine hydrocloride alone. When high dose ethanol and apomorphine hydrocloride were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject's largest drop in blood pressure measured within the 6-hour period following administration of apomorphine hydrocloride) for supine systolic and diastolic blood pressure was 9.1 mm Hg and 10.5 mm Hg, respectively [see Clinical Pharmacology (12.3) ]. The mean largest standing systolic and diastolic blood pressure decrease was 11.3 mm Hg and 12.6 mm Hg, respectively. In some individuals, the decrease was as high as 61 mm Hg and 51 mm Hg, respectively, for standing systolic and diastolic blood pressure. When low dose ethanol and apomorphine hydrocloride were concomitantly administered, the mean largest decrease in supine systolic and diastolic blood pressure was 10.2 mm Hg and 9.9 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 8.4 mm Hg and 7.1 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when apomorphine hydrocloride was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg 8.4 mm Hg, respectively. Patients should avoid drinking alcohol after using apomorphine hydrocloride [see Warnings and Precautions (5.4) ].

7.4 Dopamine Antagonists Since apomorphine hydrocloride 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 apomorphine hydrocloride. Patients with major psychotic disorders, treated with neuroleptics, should be treated with dopamine agonists only if the potential benefits outweigh the risks.

7.5 Drugs Prolonging the QT/QTc Interval Caution should be exercised when prescribing apomorphine hydrocloride concomitantly with drugs that prolong the QT/QTc interval [see Warnings and Precautions (5.10) ] .

Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Geriatric Use: In clinical trials, patients 65 years of age and older were more likely to experience certain adverse events ( 8.5 )

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of apomorphine hydrocloride in pregnant women. In animal reproduction studies, apomorphine had adverse developmental effects in rats (increased neonatal deaths) and rabbits (increased incidence of malformation) when administered during pregnancy at clinically relevant doses. These doses were also associated with maternal toxicity [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data No adverse developmental effects were observed when apomorphine (0.3, 1, or 3 mg/kg/day) was administered by subcutaneous injection to pregnant rats throughout organogenesis; the highest dose tested is 1.5 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m 2 basis. Administration of apomorphine (0.3, 1, or 3 mg/kg/day) by subcutaneous injection to pregnant rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great vessels at the mid and high doses; maternal toxicity was observed at the highest dose tested. The no-effect dose for adverse developmental effects is less than the MRHD on a mg/m 2 basis. Apomorphine (0.3, 1, or 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested, which was associated with maternal toxicity. There were no effects on developmental parameters or reproductive performance in surviving offspring. The no-effect dose for developmental toxicity (1 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

8.2 Lactation Risk Summary There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the breastfed infant, or the effects of apomorphine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for apomorphine hydrocloride and any potential adverse effects on the breastfed infant from apomorphine hydrocloride or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use In the apomorphine hydrocloride clinical development program, there were 239 patients less than age 65 treated with apomorphine hydrocloride and 311 patients who were age 65 or older. Confusion and hallucinations were reported more frequently with patients age 65 and older compared to patients with less than age 65. Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability) were also more common in patients age 65 and older. Patients age 65 and older were more likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to discontinue apomorphine hydrocloride treatment as a result of one or more adverse reactions.

8.6 Renal Impairment The starting apomorphine hydrocloride dose should be reduced in patients with mild or moderate renal impairment because the concentration and exposure (C max and AUC) are increased in these patients. Studies in subjects with severe renal impairment have not been conducted [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment Caution should be exercised when administrating apomorphine hydrocloride to patients with mild and moderate hepatic impairment because of the increased C max and AUC in these patients. Closely monitor patients with mild and moderate hepatic impairment. Studies of subjects with severe hepatic impairment have not been conducted [see Clinical Pharmacology (12.3) ] .

Apomorphine hydrocloride is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D 4 receptor, and moderate affinity for the dopamine D 2 , D 3 , and D 5 , and adrenergic α 1 D, α 2 B, α 2 C receptors. The precise mechanism of action of apomorphine hydrocloride as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D 2 -type receptors within the caudate-putamen in the brain.