Apokyn

Dosage Forms And Strengths

APOKYN 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 is used with a manual reusable, multiple-dose pen injector (APOKYN Pen). A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 0.02 mL (0.2 mg) increments. The multiple-dose pen injector is provided in a package with six needles.

Storage And Handling

APOKYN is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges.

NDC 27505-004-05

Cartons of five 3 mL cartridges

APOKYN Pen

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

Store at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F)

Distributed by: US WorldMeds, LLC 4441 Springdale Rd Louisville, KY 40241. Revised: Mar 2017

APOKYN (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. APOKYN has been studied as an adjunct to other medications.

Important Administration Instructions

APOKYN is indicated for subcutaneous administration only 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.

Premedication And Concomitant Medication

Because of the high incidence of nausea and vomiting with APOKYN treatment, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of APOKYN. Treatment with trimethobenzamide 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.

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 5HT3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated.

Dosing Information

The recommended starting dose of APOKYN is 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).

There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect 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 dose should be a 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 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), 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 the 0.2 mL (2 mg) test dose but does not respond adequately, a 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. 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.

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).

Dosing In Patients With Hepatic Impairment

Closely monitor patients with mild and moderate hepatic impairment.

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.

APOKYN is contraindicated in patients:

• Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron. There have been reports of profound hypotension and loss of consciousness when APOKYN was administered with ondansetron.
• With hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema to apomorphine or to any of the excipients including a sulfite (i.e., sodium metabisulfite). Patients with a sulfite sensitivity may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Patients who experience any hypersensitivity/allergic reaction to APOKYN should avoid taking APOKYN again.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Nausea And Vomiting

APOKYN 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 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.

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), 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.

Syncope

In clinical studies, approximately 2% of APOKYN-treated patients experienced syncope.

Hypotension / Orthostatic Hypotension

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 mmHg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension ( ≥ 30 mmHg decrease and systolic BP ≤ 90 mmHg) 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).

The hypotensive effects of APOKYN may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when using APOKYN. Check blood pressure for hypotension and orthostatic hypotension in patients using APOKYN with concomitant antihypertensive medications and/or vasodilators.

Falls

Patients with Parkinson's disease are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat Parkinson's disease. Subcutaneous APOKYN might increase the risk of falling by simultaneously lowering blood pressure and altering mobility.

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.

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.

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.

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.

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.

QTc Prolongation And Potential For Proarrhythymic Effects

There is a small dose related prolongation of QTc interval with doses of APOKYN greater than 6 mg. 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.

Withdrawal-Emergent Hyperpyrexia And Confusion

A symptom complex resembling the 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.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using APOKYN for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

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.

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.

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/m²] 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/m² 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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)

Administration With The APOKYN Pen

Instruct patients and caregivers to read the “APOKYN Pen Instructions for Use” and PATIENT INFORMATION. Instruct patients to use APOKYN only as prescribed.

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.

Avoidance Of Concomitant Antiemetic Drugs Of 5HT3 Antagonist Class

Advise patients that they should not use concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron with APOKYN. Use of APOKYN with concomitant antiemetic drugs of the 5HT3 antagonist class is contraindicated because there have been reports of profound hypotension and loss of consciousness when APOKYN was administered with ondansetron.

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. Advise patients who experience any hypersensitivity/allergic reaction to APOKYN that they should avoid taking APOKYN again.

Nausea And Vomiting

Advise patients that they may experience severe nausea and/or vomiting and that they should begin taking trimethobenzamide 300 mg orally 3 times per day for 3 days prior to starting APOKYN injections. Advise patients that APOKYN taken with trimethobenzamide may increase the risks for somnolence, dizziness, and falls. Inform patients that their healthcare provider will tell them when trimethobenzamide can be discontinued.

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) 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.

Syncope

Advise patients that APOKYN may cause syncope.

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. Instruct patients to limit their alcohol intake because it may potentiate the hypotensive effect of APOKYN.

Falls

Alert patients that they may have increased risk for falling when using APOKYN.

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.

Dyskinesia

Inform patients that APOKYN may cause and/or exacerbate pre-existing dyskinesias.

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.

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.

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.

Withdrawal-Emergent Hyperpyrexia And Confusion

Advise patients to contact their healthcare provider if they wish to discontinue APOKYN or decrease the dose of APOKYN.

Melanoma

Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to have a qualified healthcare provider examine that patient's skin periodically for melanomas on a regular basis when using APOKYN.

Priapism

Advise patients that APOKYN may cause prolonged painful erections and that if this occurs that they should seek medical attention immediately.

Injection Site Reactions

Inform patients that injections of APOKYN may result in injection site reactions including bruising, granuloma, and pruritus.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1, 0.3, or 0.8 mg/kg/day) and female (0.3, 0.8, or 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 or 23 months, respectively. In males, there was an increase in Leydig cell tumors at the highest dose tested, which is less than the MRHD (20 mg) on a mg/m² basis. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in females; the highest dose tested is similar to the MRHD on a mg/m² basis.

In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 20 mg/kg/day (male) or 40 mg/kg/day (female).

Mutagenesis

Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in vivo micronucleus assay in mice.

Impairment Of Fertility

Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the MRHD on a mg/m² basis) to male and female rats prior to and throughout the mating period and continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at all subcutaneous doses tested (0.3, 1, or 1.5 mg/kg/day); the lowest dose tested is less than the MRHD on a mg/m² basis.

In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 0.2, 0.8, or 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with use of APOKYN 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. 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/m² 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/m² 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/m² basis.

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 APOKYN and any potential adverse effects on the breastfed infant from APOKYN or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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 years of age 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.

Renal Impairment

The starting APOKYN dose should be reduced in patients with mild or moderate renal impairment because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in subjects with severe renal impairment have not been conducted.

Hepatic Impairment

Caution should be exercised when administrating APOKYN to patients with mild and moderate hepatic impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic impairment have not been conducted.

SIDE EFFECTS

The following adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

• Nausea and Vomiting
• Syncope
• Hypotension/Orthostatic Hypotension
• Falls
• Hallucinations/Psychotic-Like Behavior
• Dyskinesias
• Coronary Events
• Priapism

Clinical Trial 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). Individual APOKYN 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 APOKYN-Treated Patients in Study 1

Other Adverse Reactions

Injection Site Reactions

Patients treated with APOKYN 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 APOKYN 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.

DRUG INTERACTIONS

5HT3 Antagonists

Based on reports of profound hypotension and loss of consciousness when APOKYN was administered with ondansetron, the concomitant use of APOKYN with 5HT3 antagonists including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated.

Antihypertensive Medications And Vasodilators

The following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n = 94) compared to patients not receiving these concomitant drugs (n = 456): hypotension 10% vs 4%, myocardial infarction 3% vs 1%, serious pneumonia 5% vs 3%, serious falls 9% vs 3%, and bone and joint injuries 6% vs 2%. The mechanism underlying many of these events is unknown, but may represent increased hypotension.

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.

Drugs Prolonging the QT/QTc Interval Caution should be exercised when prescribing APOKYN concomitantly with drugs that prolong the QT/QTc interval.

Drug Abuse And Dependence

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.

Risk Summary

There are no adequate data on the developmental risk associated with use of APOKYN 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. 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/m² 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/m² 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/m² basis.

The following adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

• Nausea and Vomiting
• Syncope
• Hypotension/Orthostatic Hypotension
• Falls
• Hallucinations/Psychotic-Like Behavior
• Dyskinesias
• Coronary Events
• Priapism

Clinical Trial 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). Individual APOKYN 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 APOKYN-Treated Patients in Study 1

Other Adverse Reactions

Injection Site Reactions

Patients treated with APOKYN 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 APOKYN 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.

A 62-year-old man accidentally injected 25 mg of APOKYN subcutaneously. After 3 minutes, the patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 40/minute and a supine blood pressure of 90/50. He recovered completely within an hour.

Prolongation Of The QTc Interval

In a placebo-controlled study in which patients received increasing single doses of APOKYN from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter monitor) between APOKYN and placebo was 0 msec at 4 mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at that dose.

In a controlled trial in which patients were administered placebo or a single dose of APOKYN (mean dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between APOKYN and placebo in the change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 2 mg and 6 mg, one at 6 mg) exhibited large QTc increments ( > 60 msec from pre-dose) and had QTc intervals greater than 500 msec acutely after dosing. Doses of 6 mg or less thus are associated with minimal increases in QTc.

Decreases In Blood Pressure

Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from 3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure decrements persisted up to at least 90 minutes after dosing.

Absorption

Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 mg to 8 mg following a single subcutaneous injection of APOKYN into the abdominal wall in patients with idiopathic Parkinson's disease.

Distribution

The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later.

Metabolism And Elimination

The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes).

The route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid auto-oxidation.