Apokyn
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Questions & Answers
Side Effects & Adverse Reactions
Serious adverse events (such as intravenous crystallization of apomorphine, leading to thrombus formation and pulmonary embolism) have followed the intravenous administration of apomorphine. Consequently, apomorphine should not be administered intravenously.
The significant adverse events described below have been reported in association with the use of subcutaneous apomorphine, but almost all of them occurred during open-label, uncontrolled studies. In the development program, the controlled trial data involved relatively few patients, and examined primarily the effects of single doses. Because the background rate of many of these events in a population of patients with advanced Parkinson’s disease is unknown, it is difficult to assess the role of apomorphine in their causation.
At the recommended doses of apomorphine, severe nausea and vomiting can be expected. Because of this, in domestic clinical studies, 98% of all patients were treated with the antiemetic trimethobenzamide for three days prior to beginning apomorphine and were then encouraged to continue trimethobenzamide for at least 6 weeks. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine. 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: 0-3 years). Even with the use of trimethobenzamide in clinical trials, 31% of the patients experienced nausea and 11% of the patients experienced vomiting. In clinical trials, 3% of the patients discontinued apomorphine due to nausea and 2% discontinued due to vomiting.
In the domestic development of apomorphine, there was no experience with antiemetics other than trimethobenzamide. Some antiemetics with anti-dopaminergic actions have the potential to worsen the clinical state of patients with Parkinson’s disease and should be avoided.
In clinical studies, about 2% of patients experienced syncope.
In a study in which patients received increasing single doses of apomorphine from 2 to 10 mg (if tolerated) as well as placebo, the mean difference in QTc between apomorphine and placebo, as measured by Holter monitor, 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 apomorphine (mean dose of 5.2 mg; range of 2-10 mg, with 30 of 35 patients receiving a dose of 6 mg or less), the mean difference between apomorphine and placebo in the change in QTc was about 3 msec at 20 and 90 minutes. In the entire database, 2 patients (one at 2 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. Doses greater than 6 mg do not provide additional clinical benefit and are not recommended.
Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsades de pointes and with sudden unexplained death. The relationship of QT prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/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 apomorphine at recommended doses in premarketing 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.
Caution is recommended when administering apomorphine to patients with the risk factors described above.
Dopamine agonists may cause orthostatic hypotension at any time, especially during dose escalation. Parkinson’s disease patients, in addition, may 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.
Apomorphine causes dose-related decreases in systolic (SBP) and diastolic blood pressure (DBP). Dose-dependent mean decrements in SBP ranged from 5 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in DBP ranged from 3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 10 minutes, appeared to peak at about 20 minutes after dosing, and persisted up to at least 90 minutes post-dosing. Patients undergoing titration of apomorphine 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 apomorphine in patients with advanced Parkinson’s disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (< 1%) and resulted in withdrawal of apomorphine 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.
The effects of apomorphine on blood pressure may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Alcohol should be avoided when using APOKYN and extra caution should be exercised if APOKYN must be administered with concomitant antihypertensive medications and/or vasodilators (see PRECAUTIONS: Drug Interactions and Information for Patients).
Patients with Parkinson’s disease (PD) are at risk of falling due to the underlying postural instability and concomitant autonomic instability seen in some patients with PD, and from syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Subcutaneous apomorphine might increase the risk of falling by simultaneously lowering blood pressure and altering mobility (see WARNINGS: Symptomatic Hypotension; PRECAUTIONS: Dyskinesias).
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. Because these data were obtained in open, uncontrolled studies, and given the unknown background rate of falls in a population of patients with advanced Parkinson’s disease, it is impossible to definitively assess the contribution of apomorphine to these events.
During clinical development, hallucinations were reported by 14% of the 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 apomorphine 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 PRECAUTIONS: Drug Interactions: Dopamine Antagonists)
There have been reports in the literature of patients treated with apomorphine subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. It is clear that somnolence is commonly associated with APOKYN and many clinical experts believe 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. Prescribers should therefore continually 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, patients should be advised of the possibility that they may develop drowsiness and specifically asked 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 episodes of falling 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.
During clinical development, 4% of patients treated with apomorphine experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. Apomorphine has been shown to reduce resting systolic and diastolic blood pressure and, as such, it has the potential to exacerbate coronary (and cerebral) ischemia. Extra caution should be used in prescribing apomorphine for patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, the continued use of apomorphine should be carefully re-evaluated.
APOKYN contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
Among the 550 patients treated with apomorphine subcutaneous injections during development, 26% of patients complained of injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). There was a limited experience (both for overall numbers of patients as well as the total number of injections per patient) with apomorphine injections in controlled trials. In this limited controlled experience, the number of injection site reactions reported by patients receiving apomorphine was similar to that reported by patients receiving placebo.
There are rare reports of apomorphine abuse by patients with Parkinson’s disease in other countries. These cases are characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Psychosexual stimulation with increased libido is believed to underlie these cases. Prescribers should be vigilant for evidence that patients are abusing apomorphine, such as use out of proportion to motor signs (see DRUG ABUSE AND DEPENDENCE).
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
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) associated with advanced Parkinson’s disease. APOKYN has been studied as an adjunct to other medications (see CLINICAL PHARMACOLOGY: Clinical Studies).
History
There is currently no drug history available for this drug.
Other Information
APOKYN® (apomorphine hydrochloride, USP) is 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 • 1/2H2O. Its structural formula and molecular weight are:
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® 10 mg/mL is a clear, colorless, sterile solution for subcutaneous injection and is available in 3 mL cartridges. Each mL of solution contains 10 mg of apomorphine hydrochloride, USP as apomorphine hydrochloride hemihydrate and 1 mg of sodium metabisulfite, NF 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 and 5 mg/mL of benzyl alcohol, NF as a preservative.
Sources
Apokyn Manufacturers
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Tercica, Inc.
![Apokyn (Apomorphine Hydrochloride) Injection [Tercica, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Apokyn | Tercica, Inc.
The prescribed dose of APOKYN should always be expressed in mL to avoid confusion and doses greater than 0.6 mL (6 mg) are not recommended. Patients and caregivers must receive detailed instructions in the preparation and injection of doses, with particular attention paid to the correct use of the dosing pen (see PRECAUTIONS: Information for Patients).
APOKYN is indicated for subcutaneous administration only. APOKYN should not be initiated without use of a concomitant antiemetic (see WARNINGS: Nausea and Vomiting). Most antiemetic experience is with trimethobenzamide and this should generally be used. Trimethobenzamide (300 mg tid orally) should be started 3 days prior to the initial dose of apomorphine and continued at least during the first two months of therapy.
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, for example, ondansetron, granisetron, dolasetron, palonosetron, and alosetron) is contraindicated (see CONTRAINDICATIONS).
The dose of APOKYN must be titrated on the basis of effectiveness and tolerance, starting at 0.2 mL (2 mg) and up to a maximum recommended dose of 0.6 mL (6 mg) as follows:
Patients in an “off” state should be given a 0.2 mL (2 mg) test dose in a setting where blood pressure can be closely monitored by medical personnel. Both supine and standing blood pressure should be checked predose and at 20, 40, and 60 minutes post dose. Patients who develop clinically significant orthostatic hypotension in response to this test dose of apomorphine should not be considered candidates for treatment with APOKYN. If the patient tolerates the 0.2 mL (2 mg) dose, and responds, the starting dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing “off” episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.
Beyond this, the general principle guiding dosing (described in detail below) is to determine a dose (0.3 mL or 0.4 mL) that the patient will tolerate as a test dose under monitored conditions, and then begin an outpatient dosing trial (periodically assessing both efficacy and tolerability) using a dose 0.1 mL (1 mg) lower than the tolerated test dose.
For patients who tolerate the test dose of 0.2 mL (2 mg) but achieve no response, a dose of 0.4 mL (4 mg) may be administered at the next observed “off” period, but no sooner than 2 hours after the initial test dose of 0.2 mL (2 mg). Both supine and standing blood pressure should be checked predose and at 20, 40, and 60 minutes post dose. If the patient tolerates a test dose of 0.4 mL (4 mg) the starting dose should be 0.3 mL (3 mg) used on an as needed basis to treat existing “off” episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis. If a 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, no sooner than 2 hours after the test dose of 0.4 mL (4 mg). Both supine and standing blood pressure should be checked predose and at 20, 40, and 60 minutes post dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the starting 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.
Most patients studied in the apomorphine development program responded to 0.3 mL to 0.6 mL (3 mg to 6 mg). There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) give an increased effect and these doses are not recommended. The average frequency of dosing was 3 times per day in the development program, and 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 2.0 mL (20 mg).
If a single dose of apomorphine is ineffective for a particular “off” period, a second dose should not be given for that “off” episode. The efficacy of a second dose for a single “off” episode has not been systematically studied and the safety of redosing has not been characterized.
Patients who have a significant interruption in therapy (more than a week) should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect.
When dosing patients with mild and moderate hepatic impairment, caution should be exercised due to the increased Cmax and AUC in these patients (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
For patients with mild and moderate renal impairment, the testing dose and subsequently the starting dose should be reduced to 0.1 mL (1 mg) (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Patients should be instructed to administer apomorphine as described in the Patient Instruction Leaflets.
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Us Worldmeds, Llc
Apokyn | Us Worldmeds, Llc
2.1 Important Administration InstructionsAPOKYN is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and only by a multiple-dose APOKYN Pen with supplied cartridges. The initial dose and dose titrations should be performed by a healthcare provider. Blood pressure and pulse should be measured in the supine and standing position before and after dosing.
A caregiver or patient may administer APOKYN if a healthcare provider determines that it is appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. Because the APOKYN Pen has markings in milliliters (mL), the prescribed dose of APOKYN should be expressed in mL to avoid confusion.
Visually inspect the APOKYN drug product through the viewing window for particulate matter and discoloration prior to administration. The solution should not be used if discolored (it should be colorless), or cloudy, or if foreign particles are present. Rotate the injection site and use proper aseptic technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17)].
2.2 Premedication and Concomitant MedicationAPOKYN 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.
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)].
2.3 Dosing InformationThe 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 2hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing "off" episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis.
2.4 Dosing in Patients with Renal ImpairmentFor patients with mild and moderate renal impairment, the test dose and starting dose should be reduced to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].
2.5. Dosing in Patients with Hepatic ImpairmentClosely monitor patients with mild and moderate hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.7)].
2.6 Re-treatment and Interruption in TherapyIf 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 (Apomorphine Hydrochloride) Injection [Us Worldmeds, Llc]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=3235535d-9ef9-4657-8b2a-176a807d091c&name=apokyn-26.jpg)
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