Apokyn

Generic Name: apomorphine hydrochloride
Dosage Form: injection

Indications and Usage for Apokyn

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 [see Clinical Studies (14)].

Apokyn Dosage and Administration

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)].

Premedication and Concomitant Medication

Apokyn should be initiated with the use of a concomitant antiemetic [see Warnings and Precautions (5.2)]. Oral trimethobenzamide (300 mg three times a day) should be started 3 days prior to the initial dose of Apokyn and continued at least during the first two months of therapy.

Slideshow: Parkinson’s Disease - 10 Clinical Fast Facts

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 [see Contraindications (4)].

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) [see Clinical Studies (14)].

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 out-patient 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) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

. Dosing in Patients with Hepatic Impairment

Closely monitor patients with mild and moderate hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.7)].

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.

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.

Contraindications

Apokyn is contraindicated in patients:

  • Using concomitant drugs of the 5HT3 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 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 and 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 ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) to reduce the incidence of nausea and/or vomiting in Apokyn-treated patients 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, 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.

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) [see Clinical Pharmacology (12.2)].

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 Apokyn with concomitant antihypertensive medications and/or vasodilators [see Drug Interactions (7.2)].

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.

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.

Post marketing 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)].

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 [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.

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.

Adverse Reactions

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

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) [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.

Table 1: Adverse Reactions Occurring in Two or More Apokyn-Treated Patients in Study 1
Apokyn (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 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,s 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 [see Warnings and Precautions (5.5, 5.6)].

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 [see Warnings and Precautions (5.11)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Apokyn has been shown to be teratogenic in rabbits and embryolethal in rats when given at clinically relevant doses. Apokyn should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No adverse developmental effects were observed when apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) was administered by subcutaneous injection to pregnant rat throughout organogenesis; the highest dose tested (3 mg/kg/day) is 1.5 times the MRHD (20 mg/day) on a mg/m2 basis. Administration of apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 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 tested; the no-effect dose is less than the MRHD on a mg/m2 basis.

Apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested. 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.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Apokyn, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

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.

Overdosage

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.

Apokyn Description

Apokyn (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17H17NO2 ∙ HCL ∙ ½ H2O. Its structural formula and molecular weight are:

Figure 1: Structural Formula and Molecular Weight of Apomorphine

M.W. 312.79

Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white powder that is soluble in water at 80°C.

Apokyn is a clear, colorless, sterile solution for subcutaneous injection and is available in 3 mL (30 mg) multi-dose cartridges. Each mL of solution contains 10 mg of apomorphine hydrochloride, USP as apomorphine hydrochloride hemihydrate, 1 mg of sodium metabisulfite, NF and 5 mg of benzyl alcohol, NF (preservative) in water for injection, USP. In addition, each mL of solution may contain sodium hydroxide, NF and/or hydrochloric acid, NF to adjust the pH of the solution.

Apokyn - Clinical Pharmacology

Mechanism of Action

Apokyn is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C 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 D2-type receptors within the caudate-putamen in the brain.

Pharmacodynamics

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 msecs from pre-dose) and had QTc intervals greater than 500 msecs 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.

Pharmacokinetics

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 autooxidation.

Special Populations

The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of Parkinson's disease, levodopa dose or duration of therapy.

Renal Impairment

In a study comparing renally-impaired subjects (moderately impaired as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by approximately 16% and 50%, respectively, following a single subcutaneous administration of Apokyn into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal impairment have not been conducted. The starting dose for patients with mild or moderate renal impairment should be reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Hepatic Impairment

In a study comparing subjects with hepatic impairment (moderately impaired as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by approximately 10% and 25%, respectively, following a single subcutaneous administration of Apokyn into the abdominal wall. Studies in subjects with severe hepatic impairment have not been conducted [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].

Drug-Drug Interactions

Carbidopa/levodopa: Levodopa pharmacokinetics were unchanged when subcutaneous Apokyn and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy.

Other Drugs Eliminated Via Hepatic Metabolism

Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes.

COMT Interactions

A pharmacokinetic interaction of Apokyn with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1 mg/kg/day, 0.3 mg/kg/day, 0.8 mg/kg/day) and female (0.3 mg/kg/day, 0.8 mg/kg/day, 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 months 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 dose tested (0.3 mg/kg/day, 1 mg/kg/day, 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 mg/kg, 0.8 mg/kg, and 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.

Clinical Studies

The effectiveness of Apokyn in the acute symptomatic treatment of the recurring episodes of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of Apokyn given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant catechol-ortho-methyl transferase COMT) inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to Apokyn (i.e., Apokyn naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of Apokyn use immediately prior to study enrollment. Almost all patients without prior exposure to Apokyn began taking an antiemetic (trimethobenzamide) three days prior to starting Apokyn and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating Apokyn.

The change from baseline in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease.

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).

Table 2: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 1
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo 36.3 - 0.1 NA
Apokyn 39.7 - 23.9 - 23.8

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).

Table 3: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 2
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo 40.1 - 3.0 NA
Apokyn 41.3 - 20.0 - 17.0

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.

Table 4: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 4
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo (Pooled) 40.6 - 7.4 NA
Apokyn (Pooled) 42.0 - 24.2 - 16.8
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.

How Supplied/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) [See USP Controlled Room Temperature]

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 "Patient Information and Instructions for Use for Apokyn and the dosing pen. Instruct patients to use Apokyn only as prescribed [See Dosage and Administration (2)].

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)].

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 [see Contraindications (4)].

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 [see Contraindications (4)].

Nausea and Vomiting

Advise patients that they may experience severe nausea and/or vomiting and that they should begin taking trimethobenzamide 300 mg tablets orally 3 times per day for three days prior to starting Apokyn injections and continue taking it until told by a healthcare provider that trimethobenzamide can be discontinued [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)].

Syncope

Advise patients that Apokyn may cause syncope [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

Falls

Alert patients that they may have increased risk for falling when using Apokyn [see Warnings and Precautions (5.6)].

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 (5.7)].

Dyskinesia

Inform patients that Apokyn may cause and/or exacerbate pre-existing dyskinesias [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)].

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 [see Warnings and Precautions (5.13)].

Priapism

Advise patients that Apokyn may cause prolonged painful erections and that if this occurs that 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)].

Distributed by:

US WorldMeds, LLC
4010 Dupont Circle, Suite L-07
Louisville, KY 40207

US WorldMeds, LLC is the exclusive licensee and distributor of Apokyn in the United States and Its territories.
© 2014 Britannia Pharmaceuticals Limited. Apokyn is a registered trademark of Britannia Pharmaceuticals Limited.

Apokyn® Pen Instructions for Use

Designed to be used only with
3 mL Apokyn® (apomorphine hydrochloride injection) Cartridges

For more information, call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).

Apokyn®
(apomorphine hydrochloride injection)

Apokyn Pen

  • Apokyn® (apomorphine hydrochloride injection) is for under the skin (subcutaneous) injection only.
  • Do not inject Apokyn into a vein.
  • Do not use the Apokyn® Pen unless you and your care partner have been taught the right way and both of you understand all of the instructions.
  • The Apokyn Pen is for use only with 3 mL Apokyn® (apomorphine hydrochloride injection) Cartridges.
  • The Apokyn Pen is only for use by 1 patient and should not be shared.
Gray Pen Cap Gray Pen Body Pen Needle Unit Cartridge

a. Clip
Teal Cartridge Holder

b. Black Rod
c. White Dose Window
d. White Dose Knob
e. Teal Injection Button
f. Outer Needle Shield
g. Pink Inner Needle Shield
h. Pen Needle
i. Pink Paper Tab
j. Rubber Septum
k. Metal Cap
l. Cartridge Plunger

Read First: Important Safety Information

The Apokyn Pen is a medicine delivery device. It is very important that you or your care partner read this Instructions for Use and follow the instructions for using the Apokyn Pen correctly to receive the correct Apokyn dose.
Always perform a flow check (prime) before every injection and after loading a new cartridge.
The liquid in the Apokyn Cartridge can cause irritation if it gets on your skin or in your eyes. Flush your eyes with cold water and wash the liquid off your skin right away if this happens.
The BD pen needle unit is sterile. Avoid contaminating the needle after opening. Do not place it on a surface or touch other items with the needle.
Do not dial the dose or try to correct a dialing error with the pen needle in the skin. You could receive the wrong dose.
Be careful when removing the needle. Accidental needle sticks can transmit serious infections.

Never store or carry the Apokyn Pen with a pen needle attached.

Storing or carrying the Apokyn Pen with a pen needle attached may let:
Air enter the cartridge
Medicine leak out
This can affect your Apokyn dose.

The Apokyn Pen should only be used with pen needles (29G x 1/2"). These needles are available through your specialty pharmacy provider or your local pharmacy.

Magnification: 50× You must use a new, sterile BD pen needle with each injection.

How to Use the Apokyn Pen

Preparing the Apokyn Pen for Cartridge Loading
Step 1.
Remove the gray pen cap by pulling it straight off.
Step 2. Unscrew the teal cartridge holder from the gray pen body by turning it clockwise.

Loading a Cartridge
Step 3.
Only use Apokyn that is clear and colorless. Do not use an Apokyn Cartridge that contains medicine that is cloudy, green, or contains particles. Call your specialty pharmacy provider for replacement cartridges. Insert the Apokyn Cartridge, metal cap first, into the teal cartridge holder.

Step 4. Lower the gray pen body onto the teal cartridge holder so that the black rod presses against the cartridge plunger. Screw the teal cartridge holder onto the gray pen body. Tighten the pieces by turning the teal cartridge holder counter-clockwise until no gap remains and 1 of the white arrows line up with the white marker on the gray pen body.

Step 5. If you already have a cartridge in the pen and have used the pen, you should check the cartridge through the window in the teal cartridge holder to make sure there is enough Apokyn solution in the cartridge to provide your next dose. If the gray cartridge plunger has reached the red line on the cartridge, remove the cartridge and insert a new cartridge into the pen before attaching the pen needle and preparing the dose.

Attaching the Pen Needle
Step 6.
Remove the pink paper tab from the back of a new pen needle. Use a new needle for each injection. Never reuse needles.

Step 7. Holding the Apokyn Pen by the teal cartridge holder, push the pen needle unit onto the pen. Screw the threaded hub of the pen needle onto the teal cartridge holder counter-clockwise. When the needle unit is attached, remove the outer shield that protects the needle with a gentle pull. Save the outer shield. You will use it to remove the needle from the pen after the injection is finished. Do not remove the inner needle shield at this time. The needle is sterile and must stay clean. After opening, do not place the needle on a surface or let it touch anything.

Preparing (Priming) the Apokyn Pen for Use

IMPORTANT – Prior to each injection, it is important that the Apokyn Pen be properly primed.
For a new Apokyn Cartridge (1 that has not been used before), repeat the priming procedure described on the next page (Steps 8-9) 3 or 4 times to make sure all the air has been removed from the needle and cartridge.
For an Apokyn Cartridge you have used before (1 that has been previously primed), repeat the priming procedure described on the next page (Steps 8-9) 1 time to make sure all the air has been removed from the needle and cartridge.

Step 8. You must prepare (prime) the Apokyn Pen for use before injecting the medicine. To prime the Apokyn Pen, set the dose by turning the dose knob to 0.1 mL. This is important so you can get rid of any air bubbles in the cartridge.

Step 9. Remove the inner needle shield. Remember, do not let the needle touch any- thing. With the needle pointing up, firmly push the injection button in as far as it will go and hold for at least 5 seconds. A small stream of medicine must come out of the end of the needle. If it does not, reset the dose by repeating Step 8. Repeat these steps (Steps 8-9) until a small stream of medicine comes out the end of the needle. When medicine comes out of the end of the needle, the Apokyn Pen is primed for injection and ready to use.
Apokyn medicine can cause staining to fabric and other surfaces it touches. Be careful where you prime the Apokyn Pen.

Setting the Dose
Step 10.
To set the dose, turn the white dose knob until the correct dose (number of mLs) is shown in the window. The dose will appear as a red number between two black lines that will line up next to the letters "mL" on the pen body. Make sure the correct number (dose) appears in the window.

Step 11. Dose Correction. If you turn the dose knob past your dose, do not dial backwards. If you dial backwards, Apokyn will be pushed through the needle and you will lose medicine. Continue to turn the dial until it is fully turned. Press the injection button fully. This will reset the dial to zero without pushing medicine out of the needle. Repeat Step 10 to redial your dose.

Giving the Injection
Step 12. Apokyn
is only for injection under the skin (subcutaneous injection). Choose an injection site on your stomach area, upper arm or upper leg. Change the site with each injection. Do not inject Apokyn into skin that is red or sore.
Clean the site with an alcohol swab and allow to air dry. Pinch about an inch of skin and fat tissue of your injection site between your thumb and forefinger. With the other hand, insert the needle all the way into the pinched skin.

Step 13. Fully push the teal injection button on the Apokyn Pen. A clicking sound will be heard while the dose is injected. Push the injection button firmly for 5 seconds. Remove the needle from your skin. If medicine keeps dripping from the needle, keep the needle in the skin longer the next time you inject Apokyn.
IMPORTANT – If you set your dose and cannot depress the teal injection button, the cartridge is empty. Remove the pen needle and cartridge and prepare the pen as described in Steps 2-9 with a new cartridge. Set the dose and give the injection.
If you set your dose and the injection button stops before you receive a complete dose, note the number in the window, remove the pen needle and cartridge, and prepare the pen as described in Steps 2-9 with a new cartridge. Set the dose to the number that last appeared in the window and administer the injection. This completes the dose.
Before attempting to replace a cartridge, be sure that a needle unit is not attached to the Apokyn Pen.

Removing the Pen Needle
Step 14.
Carefully replace the outer needle shield. Be careful to avoid a needle-stick. Place the outer needle shield in the notch located on the far left side of your carrying case. The opening of the needle shield should be pointing up. Carefully insert the needle (attached to the pen) into the opening of the shield. Without holding onto the shield, push down firmly.

Step 15. Hold the pen by the teal cartridge holder and unscrew the pen needle from the cartridge holder. Recap the pen. Never recap the pen with a needle attached. Safely dispose of used pen needles in a "sharps" container. Your specialty pharmacy provider will provide you with a "sharps" container. Do not throw used needles in a trash can.

Storage Information

–Store Apokyn cartridges at room temperature, 68°F to 77°F (20°C to 25°C)

Excursions permitted to 59 to 86°F (15 to 30°C) [See USP Controlled Room Temperature]

Proper Disposal

Put your used needles and syringes in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
made of a heavy-duty plastic,
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
upright and stable during use,
leak-resistant, and
properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Care and Storage

The Apokyn Pen can now be stored in its carrying case. Never store or carry the Apokyn Pen with a pen needle attached.

You must store and care for your pen the right way:

Avoid exposure to dust, moisture, and cold or hot temperatures.
Never wash the pen in water or use strong disinfectants. Only a clean, damp cloth should be used for cleaning.
Do not try to repair the pen if it is damaged or if you cannot solve a problem shown in the following "Troubleshooting" section.
Do not use pen for more than 1 year after the first use or after the expiration date on the carton.

For more information, call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).

Troubleshooting

PROBLEM POSSIBLE CAUSE HOW TO FIX THE PROBLEM
For more information, call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).
No medicine comes out of the pen (the dosage dial moves freely, but no click is heard). The pen is in dose correction mode. Push the injection button all the way in so the dial returns to zero.
The dosage dial does not return to zero during an injection. The cartridge is empty. Replace the cartridge as described in Steps 3-5.
The pen needle is clogged. Replace the pen needle as described in Steps 14 & 6-7.  
The dosage dial does not turn easily. Dust or dirt is on the pen. Turn the dial past the highest setting on the pen. Wipe all exposed pen surfaces with a clean, damp cloth.
Pen does not close. Cartridge is inserted incorrectly. Remove cartridge and reload it. See Steps 3 - 4.
Injection button will not depress. Cartridge is empty. Replace cartridge. See Steps 3-5.
Injection button stops before a complete dose is delivered. Not enough medication in cartridge to complete the dose. Replace cartridge. See Steps 3-5.
Pen does not work. Mechanical failure. Replace pen.
Call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).
Dose numbers and/or white markers wear off. Repeated use over extended period of time. Replace pen.
Call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).
Too much force needed to depress injection button. Defective cartridge. Replace cartridge. See Steps 3-5.
Unable to read the dose numbers through the dose window. Incorrect cleaning or improper handling. Replace pen.
Call your specialty pharmacy provider or 1-877-7Apokyn (727-6596).

Patient Information

Apokyn® (AY-po-kin) (apomorphine hydrochloride injection)

Read this Patient Information before you start using Apokyn and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is Apokyn?

Apokyn is a prescription medicine used to treat acute, intermittent episodes of poor mobility called "off " episodes (end-of-dose wearing "off " or unpredictable "on -off " episodes) in people with advanced Parkinson's disease (PD).

It is not known if Apokyn is safe and effective in children.

Who should not take Apokyn?

Do not take Apokyn if you are:

  • taking certain medicines to treat nausea called 5HT3 antagonists including, ondansetron, granisetron, dolasetron, palonosetron, and alosetron. People taking ondansetron together with apomorphine, the active ingredient in Apokyn, have had very low blood pressure and lost consciousness or "blacked out."
  • allergic to apomorphine hydrochloride or to any of the ingredients in Apokyn and experience hives, itching, rash, or swelling (e.g., eyes, tongue, etc.). Apokyn also contains a sulfite called sodium metabisulfite. Sulfites can cause severe, life-threatening allergic reactions in some people. An allergy to sulfites is not the same as an allergy to sulfa. People with asthma are more likely to be allergic to sulfites. Call your healthcare provider if you have hives, itching, rash, swelling of the eyes, tongue, lips, chest pain, trouble breathing or swallowing. See the end of this leaflet for a complete list of ingredients in Apokyn.

What should I tell my healthcare provider before taking Apokyn?

Before you start using Apokyn, tell your healthcare provider if you:

  • have difficulty staying awake during the daytime
  • have dizziness
  • have fainting spells
  • have low blood pressure
  • have asthma
  • are allergic to any medicines containing sulfites
  • have liver problems
  • have kidney problems
  • have heart problems
  • have had a stroke or other brain problems
  • have a mental problem called a major psychotic disorder
  • drink alcohol
  • are pregnant or plan to become pregnant. It is not known if Apokyn will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Apokyn passes into your breast milk. You and your healthcare provider should decide if you will take Apokyn or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Using Apokyn with certain other medicines may affect each other. Using Apokyn with other medicines can cause serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I use Apokyn?

  • Read the Instructions for Use starting on page 6 of this leaflet for specific information about the right way to use Apokyn.
  • Use Apokyn exactly as your healthcare provider tells you to use it.
  • Your healthcare provider will tell you how much Apokyn to use and teach you the right way to use it.
  • Your healthcare provider may change your dose if needed.
  • Do not change your dose of Apokyn or use it more often than prescribed unless your healthcare provider has told you to.
  • Do not give another dose of Apokyn sooner than 2 hours after the last dose.
  • Your healthcare provider will prescribe Apokyn that comes in prefilled glass cartridges that are used with a special multiple-dose injector pen.
  • Your Apokyn pen is dosed in milliliters (mL), not milligrams (mg). Make sure your prescription tells you how many milliliters (mL) to use.
  • Inject Apokyn under your skin (subcutaneously). Do not inject Apokyn into a vein.
  • Keep a record of how much Apokyn you have used each time you inject or your care partner gives you an injection.
  • Use a new needle with each injection. Never reuse a needle.
  • Apokyn is a clear and colorless liquid. Do not use Apokyn if it appears cloudy, colored, or to contain particles, and call your pharmacist.
  • Your healthcare provider may prescribe another medicine called an antiemetic to take while you are using Apokyn. Antiemetic medicines help to decrease the symptoms of nausea and vomiting that can happen with Apokyn.
  • If you take too much Apokyn, call your healthcare provider. If you experience severe or serious side effects such as chest pain or prolonged erection lasting more than 4 hours, go to the nearest hospital emergency room.

What should I avoid while using Apokyn?

  • Do not drink alcohol while you are using Apokyn. It can increase your chance of developing serious side effects.
  • Do not take medicines that make you sleepy while you are using Apokyn.
  • Do not drive, operate machinery, or do other dangerous activities until you know how Apokyn affects you.
  • Do not change your body position too fast. Get up slowly from sitting or lying. Apokyn can lower your blood pressure and cause dizziness or fainting.

What are the possible side effects of Apokyn?

Apokyn may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects, including:

  • allergic reaction. An allergic reaction with side effects of hives, itching, rash, swelling (e.g., eyes, tongue, etc.); trouble breathing and/or swallowing may occur after injecting Apokyn.
  • blood clots. Injecting Apokyn into a vein (intravenous) can cause blood clots. Do not inject Apokyn in your vein.
  • nausea and vomiting. Severe nausea and vomiting can happen with Apokyn. Your healthcare provider may prescribe a medicine called trimethobenzamide (Tigan®) to help prevent nausea and vomiting. Some patients can stop taking Tigan after using Apokyn for several months. Some patients may need to keep taking Tigan to help prevent nausea and vomiting. Talk to your healthcare provider before you stop taking Tigan.
  • sleepiness or falling asleep during the day. Some people treated with Apokyn may get sleepy during the day or fall asleep without warning while doing everyday activities such as talking, eating, or driving a car.
  • dizziness. Apokyn can lower your blood pressure and cause dizziness. Dizziness can happen when Apokyn treatment is started or when the Apokyn dose is increased. Do not get up too fast from sitting or after lying down, especially if you have been sitting or lying down for a long period of time.
  • falls. The changes that can happen with Parkinson's disease (PD), and the effects of some PD medicines, can increase the risk of falling. Apokyn may also increase your risk of falling.
  • hallucinations or psychotic-like behavior. Apokyn can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking.
  • sudden uncontrolled movements (dyskinesias). Some people with PD may get sudden, uncontrolled movements after treatment with some PD medicines. Apokyn can cause or make dyskinesias worse.
  • intense urges. Some people with PD have reported new or increased gambling urges, increased sexual urges, and other intense urges, while taking PD medicines, including Apokyn.
  • heart problems. If you have shortness of breath, fast heartbeat, or chest pain while taking Apokyn, call your healthcare provider or get emergency help right away.
  • serious heart rhythm changes (QT prolongation). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint.
  • injection site problems. Bruising, swelling, and itching can happen at the site where you inject Apokyn.
  • fever and confusion. This can happen in some people when their PD medicine is stopped or there is a fast decrease in the dose of their PD medicine.
  • skin cancer (melanoma). Some people with PD may have an increased chance of getting a skin cancer called melanoma. People with PD should have a healthcare provider check their skin for skin cancer regularly.
  • tissue changes (fibrotic complications). Some people have had changes in the tissues of their pelvis, lungs, and heart valves when taking medicines called nonergot derived dopamine agonists like Apokyn.
  • prolonged painful erections (priaprism). Apokyn may cause prolonged, painful erections in some people. If you have an erection that lasts more than 4 hours you should call your healthcare provider or go to the nearest hospital emergency room right away.
  • swelling of ankles/legs. Apokyn may cause swelling, especially in the ankles or legs. Tell your healthcare provider if you notice any swelling.

Other common side effects of Apokyn include:

  • yawning
  • runny nose
  • confusion
  • swelling of your hands, arms, legs, and feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Apokyn. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Apokyn?

  • Store Apokyn at room temperature, 68°F to 77°F (20°C to 25°C).
  • Safely throw away medicine that is out of date or no longer needed.

Keep Apokyn and all medicines out of the reach of children.

General information about the safe and effective use of Apokyn.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Apokyn for a condition for which it was not prescribed. Do not give Apokyn to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Apokyn. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Apokyn that is written for health professionals.

For more information, go to www.Apokyn.com or call 1-877-727-6596.

What are the ingredients in Apokyn?

Active ingredient: apomorphine hydrochloride, USP

Inactive ingredients: sodium metabisulfite, NF, benzyl alcohol, NF, water for injection, USP. It may also contain sodium hydroxide, NF and/or hydrochloric acid, NF.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by: US WorldMeds, LLC
Louisville, KY 40207
Revised: July 2014

US WorldMeds, LLC is the exclusive licensee and distributor of Apokyn in the United States and Its territories.
© 2014 Britannia Pharmaceuticals Limited. Apokyn is a registered trademark of Britannia Pharmaceuticals Limited.

BD Medical Pharmaceutical Systems
1 Becton Drive
Franklin Lakes, NJ 07417, USA

BD and BD Logo are trademarks of Becton, Dickinson and Company.
©2009 BD

PRINCIPAL DISPLAY PANEL - 30 mg/3 mL Cartridge Carton

NDC 27505-004-05
5 X 3 mL Cartridges

Apokyn®
(apomorphine hydrochloride injection)

For use only with the Apokyn®Pen for
subcutaneous administration.
Not for Intravenous Use.

Rx only

30 mg/3 mL
(10 mg/mL)

US WorldMeds

Apokyn 
apomorphine hydrochloride injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:27505-004
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
APOMORPHINE HYDROCHLORIDE (APOMORPHINE) APOMORPHINE HYDROCHLORIDE 30 mg  in 3 mL
Inactive Ingredients
Ingredient Name Strength
sodium metabisulfite 3 mg  in 3 mL
benzyl alcohol 15 mg  in 3 mL
water  
sodium hydroxide  
hydrochloric acid  
Packaging
# Item Code Package Description
1 NDC:27505-004-05 5 CARTRIDGE in 1 CARTON
1 NDC:27505-004-01 3 mL in 1 CARTRIDGE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021264 07/02/2004
Labeler - US WorldMeds, LLC (087875626)
Establishment
Name Address ID/FEI Operations
Vetter Pharma Fertigung GmbH & Co. KG 316126754 MANUFACTURE(27505-004)
Revised: 08/2014
 
US WorldMeds, LLC
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