2.1 Important Administration Instructions

APOKYN is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and only by a multiple-dose APOKYN Pen with supplied cartridges. The initial dose and dose titrations should be performed by a healthcare provider. Blood pressure and pulse should be measured in the supine and standing position before and after dosing.

A caregiver or patient may administer APOKYN if a healthcare provider determines that it is appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. Because the APOKYN Pen has markings in milliliters (mL), the prescribed dose of APOKYN should be expressed in mL to avoid confusion.

Visually inspect the APOKYN drug product through the viewing window for particulate matter and discoloration prior to administration. The solution should not be used if discolored (it should be colorless), or cloudy, or if foreign particles are present. Rotate the injection site and use proper aseptic technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17)] .

2.2 Premedication and Concomitant Medication

Because of the incidence of nausea and vomiting with APOKYN, it is recommended that treatment with trimethobenzamide 300 mg three times a day be started 3 days prior to the initial dose of APOKYN [see Warnings and Precautions (5.2)] . Alternatively, consider starting APOKYN therapy at 0.1 mL (1 mg) and titrate based upon effectiveness and tolerance.

If trimethobenzamide is used, it should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with APOKYN, as trimethobenzamide increases the incidence of somnolence, dizziness, and falls in patients treated with APOKYN [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 3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated [see Contraindications (4)].

2.3 Dosing Information

The recommended starting dose of APOKYN is 0.1 mL (1 mg) to 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) [see Clinical Studies (14)] .

There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect Reference ID: 5002510 - 3 - and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg).

Begin dosing when patients are in an "off" state. The initial test dose should be a 0.1 mL (1 mg) or 0.2 mL (2 mg) test dose in a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who develop clinically significant orthostatic hypotension in response to this test dose of APOKYN should not be considered candidates for treatment with APOKYN.

If the patient tolerates the initial test dose, and responds adequately, the starting dose should be the same as the test dose, used on an as needed basis to treat recurring "off" episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.

If the patient tolerates a 0.1 mL (1 mg) test dose but does not respond adequately, a test dose of 0.2 mL (2 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, at the next observed "off" period. If the patient tolerates a 0.2 mL (2 mg) test dose but does not respond adequately, a test dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, at the next observed "off" period. Patients who do not tolerate 0.2 mL (2 mg) may need to be titrated slowly. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring "off" episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate "off" period under medical supervision, at least 2 hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing "off" episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis.

2.4 Dosing in Patients with Renal Impairment

For patients with mild and moderate renal impairment, the test dose and starting dose should be reduced to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)] .

2.5 Re-treatment and Interruption in Therapy

If a single dose of APOKYN is ineffective for a particular "off" period, a second dose should not be given for that "off" episode. The efficacy of the safety of administering a second dose for a single "off" episode has not been studied systematically. Do not administer a repeat dose of APOKYN sooner than 2 hours after the last dose.

Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect and tolerability.

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.

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 APOKYN. 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 (APOKYN 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 APOKYN-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 APOKYN doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of APOKYN. 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 (5.8)]

7.1 5HT 3 Antagonists

Based on reports of profound hypotension and loss of consciousness when APOKYN was administered with ondansetron, the concomitant use of APOKYN 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 APOKYN in healthy subjects causes greater decreases in blood pressure compared to APOKYN alone. When nitroglycerin and APOKYN 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 APOKYN) 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 APOKYN 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 APOKYN 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 APOKYN in healthy subjects causes greater decreases in blood pressure compared to APOKYN alone.

When high dose ethanol and APOKYN 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 APOKYN) 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 APOKYN 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 APOKYN 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 APOKYN [see Warnings and Precautions (5.4)].

7.4 Dopamine Antagonists

Since APOKYN 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 APOKYN. 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 APOKYN concomitantly with drugs that prolong the QT/QTc interval [see Warnings and Precautions (5.11)] .

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 the APOKYN clinical development program, there were 239 patients less than age 65 treated with APOKYN 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 APOKYN treatment as a result of one or more adverse reactions.

8.6 Renal Impairment

The starting APOKYN 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 APOKYN 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)] .

9.2 Abuse

In premarketing clinical experience, APOKYN 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 APOKYN or levodopa. In general, these reports consist of patients taking increasing doses of medication in order to achieve a euphoric state.

12.1 Mechanism of Action

APOKYN 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 1D, α 2B, α 2C receptors. The precise mechanism of action of APOKYN 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of "off" time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of APOKYN or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a "therapeutic response" (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of APOKYN or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of APOKYN) or placebo equivalent.

Of the 20 patients randomized to APOKYN, 18 achieved a "therapeutic response" at about 20 minutes. The mean APOKYN dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a "therapeutic response." The mean change from baseline for UPDRS Part III score for APOKYN group (highest dose) was statistically significant compared to that for the placebo group (Table 2).

Study 2

Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using APOKYN for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous APOKYN (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of APOKYN was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change from baseline UPDRS Part III score for the APOKYN group was statistically significant compared to that for the placebo group (Table 3).

Study 3

Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (APOKYN-35; Placebo-27) with Parkinson's disease who had been using APOKYN for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: APOKYN at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual APOKYN dose, APOKYN at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual APOKYN dose + 0.2 mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. APOKYN doses ranged between 2 mg – 10 mg. The mean change from baseline for the APOKYN group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled APOKYN and placebo administration.

Figure 2: Mean Change from Baseline in UPDRS Motor Scores of Pooled APOKYN Groups and Placebo Group in Study 3

In Study 3, the mean changes from baseline for UPDRS Part III scores at 20 minutes post dosing for the APOKYN and higher dose APOKYN groups were 24 and 25, respectively. This result suggests that patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment of 2 mg. There was also an increased incidence of adverse reactions in patients randomized to higher APOKYN dose.

APOKYN Pen

The pen injector is provided in a package with five needles and a carrying case.

Store at 25°C (77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]

Administration with the APOKYN Pen

Instruct patients and caregivers that the APOKYN Pen is dosed in milliliters, not milligrams.

Inform patients and caregivers that it is possible to dial in their usual dose of APOKYN even though the cartridge may contain less than that amount of drug. In this case, they will receive only a partial dose with the injection, and the amount left to inject will appear in the dosing window. To complete the correct dose, patients/caregivers will need to "re-arm" the device and dial in the correct amount of the remaining dose. Patients and caregivers should be alerted to the fact that there may be insufficient drug left in the cartridge to deliver a complete dose (for example, patients and caregivers should be urged to keep records of how many doses they have delivered for each cartridge, so that they can replace any cartridge that has an inadequate amount of drug remaining).

Instruct patients to rotate the injection site and to observe proper aseptic technique.

Advise patients that APOKYN is intended only for subcutaneous injection 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 reaction characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of APOKYN 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 APOKYN that they should not take APOKYN again [see Contraindications (4)].

Nausea and Vomiting

Advise patients they may experience nausea and/or vomiting, which may be severe, and that treatment with oral trimethobenzamide 300 mg 3 times per day for 3 days prior to starting APOKYN injections has been used to help minimize these symptoms. Alternatively, starting APOKYN at a lower dose and titrating based on individual tolerance and treatment effect may be attempted. Advise patients that APOKYN taken with trimethobenzamide may increase the risks 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 APOKYN, 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 APOKYN 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. Because of possible additive effects of alcohol use, advise patients to limit their alcohol intake [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 after taking APOKYN. Inform patients that alcohol and nitroglycerin (and possibly other vasodilators and antihypertensive medications) may potentiate the hypotensive effect of APOKYN [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 taking APOKYN to avoid alcohol while using APOKYN and of the increased hypotensive effects of APOKYN taken with nitroglycerin or by taking APOKYN after alcohol ingestion.

Falls

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

Hallucinations and/or Psychotic-Like Behavior

Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur. Tell patients if they have a major psychotic disorder, ordinarily they should not use APOKYN because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of APOKYN [see Warnings and Precautions (5.6)] .

Dyskinesia

Inform patients that APOKYN may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.7)].

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 (5.8)] .

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 taking APOKYN [see Warnings and Precautions (5.9)] .

Coronary Events

Inform patients that APOKYN may cause coronary events including angina and myocardial infarction and these outcomes could possibly be related to significant hypotension/orthostatic hypotension [see Warnings and Precautions (5.10)].

QTc Prolongation and Potential for Proarrhythymic Effects

Alert patients that APOKYN 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 (5.11)].

Withdrawal-Emergent Hyperpyrexia and Confusion

Advise patients to contact their healthcare provider if they wish to discontinue APOKYN or decrease the dose of APOKYN [see Warnings and Precautions (5.12)].

Priapism

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

Injection Site Reactions

Inform patients that injections of APOKYN may result in injection site reactions including bruising, granuloma, and pruritus [see Adverse Reactions (6.1)].