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Pronunciation
(a poe MOR feen)
Generic Available (U.S.)
No
Index Terms
Prescribing and Access Restrictions
Apokyn® is only available through a select group of specialty pharmacies and cannot be obtained through a retail pharmacy. Apokyn® may be obtained from the following specialty pharmacies: Accredo Nova Factor or PharmaCare. To obtain the medication, contact the APOKYN Call Center at 1-877-7APOKYN (1-877-727-6596).
Brand Names: U.S.
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypomobility, “off” episodes with Parkinson's disease
Use: Unlabeled/Investigational
Treatment of erectile dysfunction
Pregnancy Risk Factor
C
Pregnancy Considerations
Reproduction studies have not been conducted; use only if clearly needed.
Lactation
Excretion in breast milk unknown/contraindicated
Contraindications
Hypersensitivity to apomorphine or any component of the formulation; concomitant use with 5HT3 antagonists; intravenous administration
Warnings/Precautions
Concerns related to adverse effects:
• Hallucinations/psychosis: May cause hallucinations or psychotic-like behavior or thoughts (eg. paranoia, delusions, confusion, aggression, agitation, delirium); avoid in patients with major psychotic disorders.
• Impulse control disorders: Dopamine agonists used for Parkinson's disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), and/or binge eating. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.
• Melanoma: Risk for melanoma development is increased in Parkinson's disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.
• Orthostatic hypotension: May cause orthostatic hypotension; Parkinson's disease patients appear to have an impaired capacity to respond to a postural challenge. Use with caution in patients at risk of hypotension (such as those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson's patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and should be informed of this risk. Orthostasis peaks 20 minutes after dosing and lasts at least 90 minutes. If patient develops clinically-significant orthostatic hypotension with test dose, then apomorphine should not be used.
• Pleural/retroperitoneal fibrosis: Ergot-derived dopamine agonists have also been associated with fibrotic complications (eg, retroperitoneal fibrosis, pleural thickening, and pulmonary infiltrates); monitor closely for signs and symptoms of fibrosis.
• Retinal changes: Pathologic degenerative changes were observed in the retinas of albino rats during studies with this agent, but were not observed in the retinas of albino mice or in other species. The significance of these data for humans remains uncertain.
• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs. Monitor for daytime somnolence or pre-existing sleep disorder; caution with concomitant sedating medication; discontinue if significant daytime sleepiness or episodes of falling asleep occur. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease; hypotension may cause coronary ischemia.
• Cerebrovascular disease: Use with caution in patients with cerebrovascular disease; hypotension may cause cerebral ischemia.
• Dyskinesias: Use with caution in patients with pre-existing dyskinesias; may be exacerbated.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Patients at risk for torsade de pointes: Use with caution in patients with risk factors for torsade de pointes (hypokalemia, hypomagnesemia, bradycardia, concurrent use of drugs that prolong QTc, or genetic predisposition).
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Antiemetic pretreatment: Pretreatment with antiemetic is necessary; avoid pretreatment with antidopaminergic and antiserotonin antiemetic agents (antiemetic experience is greatest with trimethobenzamide).
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Dosage form specific issues:
• Metabisulfite: Contains metabisulfite which may cause allergic reactions in some individuals.
Other warnings/precautions:
• Abuse: Rare cases of abuse have been reported.
• Appropriate administration: Do not give intravenously; thrombus formation or pulmonary embolism may occur.
• Discontinuation of therapy: Dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal or significant dosage reduction after long-term use.
Adverse Reactions
>10%:
Cardiovascular: Chest pain/pressure or angina (15%)
Central nervous system: Drowsiness or somnolence (35%), dizziness or orthostatic hypotension (20%)
Gastrointestinal: Nausea and/or vomiting (30%)
Neuromuscular & skeletal: Falls (30%), dyskinesias (24% to 35%)
Respiratory: Yawning (40%), rhinorrhea (20%)
1% to 10%:
Cardiovascular: Edema (10%), vasodilation (3%), hypotension (2%), syncope (2%), CHF
Central nervous system: Hallucinations or confusion (10%), anxiety, depression, fatigue, headache, insomnia, pain
Dermatologic: Bruising
Endocrine & metabolic: Dehydration
Gastrointestinal: Constipation, diarrhea
Local: Injection site reactions
Neuromuscular & skeletal: Arthralgias, weakness
Miscellaneous: Diaphoresis increased
<1%: Aggression, agitation, angina, cardiac arrest, confusion, focal panniculitis, libido increased, MI, paranoia, priapism, psychosexual stimulation, psychosis (acute), skin nodules, sudden death
Postmarketing and/or case reports: Reported with dopamine agonists: Impulsive/compulsive behaviors (eg, pathological gambling, hypersexuality, binge eating)
Metabolism/Transport Effects
Substrate of COMT, CYP1A2 (minor), CYP2C19 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C19 (weak), CYP3A4 (weak)
Drug Interactions
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the hypotensive effect of Apomorphine. Risk X: Avoid combination
Antipsychotics (Atypical): May diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification
Antipsychotics (Typical): Anti-Parkinson's Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotics (Typical). Antipsychotics (Typical) may enhance the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson's agents. Risk D: Consider therapy modification
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
COMT Inhibitors: May decrease the metabolism of COMT Substrates. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Indacaterol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk C: Monitor therapy
Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Caution with ethanol consumption; may increase risk of hypotension.
Storage
Store at 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Stimulates postsynaptic D2-type receptors within the caudate putamen in the brain.
Pharmacodynamics/Kinetics
Onset of action: SubQ: Rapid
Distribution: Vd: Mean: 218 L
Metabolism: Not established; potential routes of metabolism include sulfation, N-demethylation, glucuronidation, and oxidation; catechol-O methyltransferase and nonenzymatic oxidation. CYP isoenzymes do not appear to play a significant role.
Half-life elimination: Terminal: 40 minutes
Time to peak, plasma: Improved motor scores: 20 minutes
Excretion: Urine 93% (as metabolites); feces 16%
Dosage
SubQ: Adults: Begin antiemetic therapy 3 days prior to initiation and continue for 2 months before reassessing need.
Parkinson's disease, “off” episode: Initial test dose 2 mg, medical supervision required; see “Note”. Subsequent dosing is based on both tolerance and response to initial test dose.
If patient tolerates test dose and responds: Starting dose: 2 mg as needed; may increase dose in 1 mg increments every few days; maximum dose: 6 mg
If patient tolerates but does not respond to 2 mg test dose: Second test dose: 4 mg
If patient tolerates and responds to 4 mg test dose: Starting dose: 3 mg, as needed for “off” episodes; may increase dose in 1 mg increments every few days; maximum dose 6 mg
If patient does not tolerate 4 mg test dose: Third test dose: 3 mg
If patient tolerates 3 mg test dose: Starting dose: 2 mg as needed for “off” episodes; may increase dose in 1 mg increments to a maximum of 3 mg
If therapy is interrupted for >1 week, restart at 2 mg and gradually titrate dose.
Note: Medical supervision is required for all test doses with standing and supine blood pressure monitoring predose and 20-, 40-, and 60 minutes postdose. If subsequent test doses are required, wait >2 hours before another test dose is given; next test dose should be timed with another “off” episode. If a single dose is ineffective for a particular “off” episode, then a second dose should not be given. The average dosing frequency was 3 times/day in the development program with limited experience in dosing >5 times/day and with total daily doses >20 mg. Apomorphine is intended to treat the “off” episodes associated with levodopa therapy of Parkinson's disease and has not been studied in levodopa-naive Parkinson's patients.
Dosage adjustment in renal impairment:
Mild-to-moderate impairment: Reduce test dose and starting dose: 1 mg
Severe impairment: Has not been studied
Dosage adjustment in hepatic impairment:
Mild-to-moderate impairment: Use caution
Severe impairment: Has not been studied
Administration: I.V.
Not for I.V. administration.
Administration: Other
SubQ: Initiate antiemetic 3 days before test dose of apomorphine and continue for 2 months (if patient to be treated) before reassessment. Administer in abdomen, upper arm, or upper leg; change site with each injection. 3 mL cartridges are used with a manual, reusable, multidose injector pen. Injector pen can deliver doses up to 1 mL in 0.02 mL increments. Do not give intravenously; thrombus formation or pulmonary embolism may occur.
Monitoring Parameters
Each test dose: Supine and standing blood pressure predose and 20, 40, and 60 minutes postdose; drowsiness
Patient Education
Follow specific directions for administration with injection pen or syringe and needle disposal. Avoid alcohol. An antiemetic may be prescribed to reduce nausea or vomiting. May cause headache, drowsiness, dizziness, loss of impulse control (possibly manifested as pathological gambling, libido increases, and/or binge eating), postural hypotension, nausea, or vomiting. Report immediately any irregular or rapid heartbeat, chest pain, palpitations, difficulty breathing, or shortness of breath; unusual or sudden sleepiness; unusual muscle or skeletal movements or weakness, tremors, or altered gait; CNS changes (hallucinations, confusion, insomnia, anxiety, or depression); suicide ideation; redness, swelling, or irritation at injection site; changes in the appearance of skin moles; or other unusual skin changes.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Orthostatic hypotension has been reported in significant numbers of patients.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Apomorphine is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Apomorphine is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Apomorphine is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Nursing: Physical Assessment/Monitoring
Patient must be monitored closely for minimum of 90 minutes following each test dose. Monitor for orthostatic hypotension, nausea, vomiting, dyskinesias, and excessive sedation or somnolence. Teach patient or caregiver proper injection technique and needle disposal.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as hydrochloride:
Apokyn®: 10 mg/mL (3 mL) [contains benzyl alcohol, sodium metabisulfite]
References
Factor SA, “Current Status of Symptomatic Medical Therapy in Parkinson's Disease,” Neurotherapeutics, 2008, 5(2):164-80.
Molina JA, Sàinz-Artiga MJ, Fraile A, et al, “Pathologic Gambling in Parkinson's Disease: A Behavioral Manifestation of Pharmacologic Treatment,” Mov Disord, 2000, 15(5):869-72.
Weintraub D, Siderowf AD, Potenza MN, et al, “Association of Dopamine Agonist Use With Impulse Control Disorders in Parkinson Disease,” Arch Neurol, 2006, 63(7):969-73.
International Brand Names
Lexi-Comp.com
Last full review/revision December 2011
Content last modified December 2011
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