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Apomorphine

Pronunciation

(a poe MOR feen)

Index Terms

  • Apomorphine Hydrochloride
  • Apomorphine Hydrochloride Hemihydrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Subcutaneous, as hydrochloride:

Apokyn: 10 mg/mL (3 mL) [contains benzyl alcohol, sodium metabisulfite]

Brand Names: U.S.

  • Apokyn

Pharmacologic Category

  • Anti-Parkinson Agent, Dopamine Agonist

Pharmacology

Stimulates postsynaptic D2-type receptors within the caudate putamen in the brain.

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

Onset of Action

SubQ: Rapid

Time to Peak

Plasma: 10 to 60 minutes

Half-Life Elimination

Terminal: ~40 minutes

Special Populations: Renal Function Impairment

Cmax was increased by 50% in patients with moderate renal impairment.

Special Populations: Hepatic Function Impairment

Cmax was increased by 25% in patients with moderate hepatic impairment.

Use: Labeled Indications

Parkinson disease: Treatment of hypomobility “off” episodes with advanced Parkinson disease

Contraindications

Hypersensitivity to apomorphine or any component of the formulation; concomitant use with 5-HT3 antagonists

Dosing: Adult

Begin antiemetic therapy 3 days prior to initiation and continue for 2 months before reassessing need; apomorphine is intended to be used as adjunctive therapy with other anti-Parkinson agents.

Parkinson disease, “off” episode: SubQ: 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; after a few days, may increase dose up to 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 (and after 60 minutes, if there is significant hypotension at 60 minutes). 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, single doses >6 mg, and with total daily doses >20 mg.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild-to-moderate impairment: Initial test dose: 1 mg; Starting dose: 1 mg as needed

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild-to-moderate impairment: No dosage adjustment necessary; use caution

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

SubQ: For subcutaneous administration only; do not administer IV (thrombus formation or pulmonary embolism may occur due to IV crystallization). Administer in abdomen, upper arm, or upper leg; change site with each injection. Three 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride: Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Amisulpride may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Antiemetics (5HT3 Antagonists): May enhance the hypotensive effect of Apomorphine. Avoid combination

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson 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 agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Monitor therapy

COMT Inhibitors: May decrease the metabolism of COMT Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Adverse Reactions

Note: Frequency not always defined.

>10%:

Cardiovascular: Angina pectoris (15%), chest pain (15%), chest pressure (15%)

Central nervous system: Drowsiness (35%), dizziness (20%), orthostatic hypotension (20%)

Gastrointestinal: Nausea (30%), vomiting (30%)

Neuromuscular & skeletal: Dyskinesia (24% to 35%), falling (30%)

Respiratory: Yawning (40%), rhinorrhea (20%)

1% to 10%:

Cardiovascular: Edema (10%), vasodilatation (3%), hypotension (2%), syncope (2%), congestive heart failure

Central nervous system: Confusion (10%), hallucinations (10%), anxiety, depression, fatigue, headache, insomnia, pain

Dermatologic: Bruise

Endocrine & metabolic: Dehydration

Gastrointestinal: Constipation, diarrhea

Local: Injection site reaction

Neuromuscular & skeletal: Arthralgia, weakness

Miscellaneous: Diaphoresis

<1% (Limited to important or life-threatening): Aggressive behavior, agitation, cardiac arrest, confusion, hemolytic anemia (combination therapy, Colosimo 1994; Frankel 1990), impulse control disorder, impulsivity, increased libido, myocardial infarction, panniculitis (focal), paranoia, priapism, psychosis (acute)

Warnings/Precautions

Concerns related to adverse effects:

• GI effects: Severe nausea and vomiting may occur. Pretreatment with antiemetic (eg, trimethobenzamide) is necessary and should be started 3 days prior to initiation of therapy and continued at least during the first 60 days of therapy; avoid use of antidopaminergic antiemetic agents (eg, promethazine, prochlorperazine, chlorpromazine, metoclopramide or haloperidol).

• Hallucinations/psychosis: May cause hallucinations or psychotic-like behavior or thoughts (eg, paranoia, delusions, confusion, disorientation, aggression, agitation, delirium) which may be severe; avoid in patients with major psychotic disorders.

• Hypersensitivity: If a hypersensitivity/allergic reaction to apomorphine occurs, discontinue therapy and do not rechallenge.

• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), binge eating, and/or other intense urges. 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 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/syncope: May cause orthostatic hypotension, especially during dose escalation, and syncope. Parkinson 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 concomitant ethanol consumption) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Carefully monitor for signs and symptoms of postural hypotension (especially during dose escalation). Avoid ethanol during therapy.

• Pleural/retroperitoneal fibrosis: Ergot-derived dopamine agonists have also been associated with fibrotic complications (eg, retroperitoneal fibrosis, pleural thickening, cardiac valvulopathy, and pulmonary infiltrates); monitor closely for signs and symptoms of fibrosis; effects may or may not be reversible.

• Priapism: Has been reported; severe priapism may require medical attention.

• Somnolence: Somnolence and falling asleep while engaging in activities of daily living, without prior warning signs, has been reported. Monitor for daytime somnolence or preexisting 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 preexisting dyskinesias; may be exacerbated.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Adverse effects (confusion and hallucinations), some serious, are reported more frequently in patients ≥65 years; use with caution.

• Patients at risk for torsades de pointes: Use with caution in patients with risk factors for torsades de pointes (hypokalemia, hypomagnesemia, bradycardia, concurrent use of drugs that prolong QTc, or genetic predisposition).

Dosage form specific issues:

• Benzyl alcohol: Injection may contain benzyl alcohol which has been associated with "gasping syndrome" in neonates.

• Metabisulfite: Contains metabisulfite which may cause allergic reactions in some individuals.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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 (eg, hyperpyrexia, confusion) on abrupt withdrawal or significant dosage reduction after long-term use.

• Falling: Patients with Parkinson disease are at risk of falling; apomorphine may increase this risk.

Monitoring Parameters

Supine and standing blood pressure and pulse predose and 20, 40, and 60 minutes postdose with each test dose; signs and symptoms of orthostatic hypotension; drowsiness or sleepiness; mental status and behavioral changes; periodic skin examinations.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinorrhea, yawning, injection site irritation, fatigue, flushing, or pale skin. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), severe dizziness, passing out, confusion, severe nausea, severe vomiting, skin growths, mole changes, uncontrollable urges, mood changes, behavioral changes, abnormal movements, hallucinations, sweating a lot, abnormal heartbeat, severe headache, shortness of breath, excessive weight gain, swelling of arms or legs, angina, narcolepsy, tachycardia, or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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