Apomorphine (Monograph)

Brand name: Apokyn
Drug class: Nonergot-derivative Dopamine Receptor Agonists
VA class: CN500
Chemical name: 5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol hydrochloride
Molecular formula: C₁₇H₁₇NO₂•HCl•½H₂O
CAS number: 41372-20-7

Medically reviewed by Drugs.com on Apr 27, 2022. Written by ASHP.

Introduction

Nonergot-derivative dopamine receptor agonist.

Uses for Apomorphine

Parkinson Disease

Used sub-Q for acute, intermittent treatment of episodes of hypomobility (i.e., “off” episodes, including end-of-dose “wearing off” and unpredictable “on-off” episodes) associated with advanced parkinson disease (designated an orphan drug by FDA for this use).

Used as an adjunct to other antiparkinsonian agents (e.g., levodopa, dopamine receptor agonists).

Following sub-Q administration, provides rapid relief of parkinsonian symptoms, usually within 10–20 minutes, but has a short duration of action (about 60 minutes). Therefore, used principally as a rescue treatment for patients experiencing sudden wearing-off episodes despite optimized treatment with oral antiparkinsonian agents.

Although not FDA-labeled for use as a continuous sub-Q infusion^{† [off-label]}, has been used effectively and safely in this manner; current evidence indicates that sub-Q infusion of apomorphine can substantially reduce “off” time in patients with persistent motor fluctuations not controlled by optimized oral therapies.

Apomorphine Dosage and Administration

General

• Administer an antiemetic (i.e., trimethobenzamide hydrochloride 300 mg orally 3 times daily) beginning 3 days prior to initiation of apomorphine; continue for the first 2 months of therapy or until tolerance to nausea and vomiting develops.

• Avoid certain other antiemetic agents (i.e., selective 5-HT₃ receptor antagonists, dopamine-receptor antagonists [metoclopramide, phenothiazines]). (See Contraindications under Cautions and Specific Drugs under Interactions.)

Administration

Administer by sub-Q injection. Do not administer IV; possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism). (See IV Administration under Cautions.)

Also has been administered as a continuous sub-Q infusion^{† [off-label]}.

Sub-Q Administration

Administer by sub-Q injection using the dosing pen (with supplied cartridges) on an as-needed basis.

Administer sub-Q injections in the abdomen, thigh, or upper arm; rotate injection sites.

Separate administration of doses by at least 2 hours.

Test dose: Administer all test doses in a medical setting where BP can be closely monitored. Measure supine and standing BP prior to and 20, 40, and 60 minutes after each test dose. Begin dosing when patient is experiencing an “off” episode. Induction of an “off” state can be facilitated by withholding the patient’s antiparkinsonian agents overnight.

Dosage

Available as apomorphine hydrochloride; dosage expressed in terms of the salt.

Provide dosing instructions in mL to minimize dosing errors; dose on the dosing pen device is expressed in terms of mL.

Titrate dose according to patient response and tolerance.

Adults

Parkinson Disease

Sub–Q

Initial test dose is 0.2 mL (2 mg). If the 0.2-mL (2-mg) dose is effective and tolerated, this dose may be used on an as-needed, outpatient basis. If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.

Patient is not a candidate for apomorphine therapy if clinically significant orthostatic hypotension occurs in response to initial 0.2-mL (2-mg) test dose.

For patients who tolerate, but do not respond to the initial 0.2-mL (2-mg) test dose, administer a second test dose of 0.4 mL (4 mg) at the next observed “off” period, no sooner than 2 hours after the initial test dose. If the 0.4-mL (4-mg) dose is effective and tolerated, a 0.3-mL (3-mg) dose may be used on an as-needed, outpatient basis. If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.

For patients who respond, but do not tolerate the 0.4-mL (4-mg) test dose, administer a third test dose of 0.3 mL (3 mg) at the next observed “off” period, but no sooner than 2 hours after the 0.4-mL (4-mg) test dose. If the 0.3-mL (3-mg) dose is effective and tolerated, a 0.2-mL (2-mg) dose may be used on an as-needed, outpatient basis. If the 0.2-mL (2-mg) dose is tolerated, the dose may be increased, if needed, to 0.3 mL (3 mg) after a few days. The dose should not usually be increased to 0.4 mL (4 mg) on an outpatient basis in these patients.

If therapy has been interrupted for >1 week, reinitiate at a dose of 0.2 mL (2 mg) and gradually titrate to effect.

Prescribing Limits

Adults

Parkinson Disease

Sub-Q

No more than one dose of apomorphine should be administered for treatment of a single “off” episode. Safety and efficacy of a second dose during the same “off” episode in patients not responding to the initial dose have not been established. A repeat dose should not be administered sooner than 2 hours after the last dose.

Doses >0.6 mL (6 mg) not associated with additional therapeutic effect and are not recommended.

Limited experience with >5 doses per day or daily dosages >2 mL (20 mg).

Special Populations

Hepatic Impairment

No special recommendations for patients with hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

In patients with mild or moderate renal impairment, reduce initial test dose and subsequent starting dose to 0.1 mL (1 mg). (See Renal Impairment under Cautions.)

Cautions for Apomorphine

Contraindications

• Concomitant use with selective 5-HT₃ receptor antagonists. (See Specific Drugs under Interactions.)

• Known hypersensitivity to apomorphine hydrochloride or any ingredient in the formulation (e.g., sodium metabisulfite).

Warnings/Precautions

Warnings

IV Administration

Thrombus formation and pulmonary embolism reported following IV administration. Do not administer IV.

Nausea and Vomiting

Severe nausea and vomiting expected; concomitant use of an antiemetic recommended. Trimethobenzamide was used in clinical studies; other antiemetics are contraindicated (i.e., 5-HT₃ receptor antagonists) or not recommended (i.e., dopamine-receptor antagonists). (See General under Dosage and Administration and Specific Drugs under Interactions.)

Trimethobenzamide has been shown to reduce nausea and vomiting during first 4 weeks of apomorphine treatment, but can increase risk of somnolence, dizziness, and falls. Therefore, balance risks versus benefits. Limit duration of trimethobenzamide therapy to shortest amount of time necessary to control nausea and vomiting (generally no longer than 2 months).

Falling Asleep During Activities of Daily Living and Somnolence

Falling asleep while engaged in activities of daily living reported. While somnolence occurs frequently in patients receiving apomorphine, these patients perceived no warning signs and believed they were alert immediately prior to the event. Falling asleep while engaged in activities of daily living is thought to always occur in a setting of preexisting somnolence, although patients may not give such a history.

Continually reassess patients for drowsiness or sleepiness. Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities. Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, the presence of sleep disorders).

In general, discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating). If the drug is continued, advise patients to not drive and to avoid other potentially dangerous activities. Insufficient information to establish whether dosage reduction will eliminate this adverse effect.

Symptomatic Hypotension

Dopamine agonists appear to impair systemic regulation of BP, resulting in postural/orthostatic hypotension, especially during dosage escalation. Orthostatic hypotension, hypotension, and/or syncope reported in clinical studies with apomorphine. Orthostatic hypotension can also be a manifestation of parkinson disease.

Monitor patients for signs and symptoms of orthostatic hypotension, particularly during dosage escalation.

Prolongation of QT Interval

Risk of QT-interval prolongation with doses >6 mg. Such doses do not provide additional clinical benefit and should not be used.

Consider risks versus benefits in patients with risk factors for QT-interval prolongation (e.g., congenital or known QT-interval prolongation, clinically important bradycardia, hypokalemia, hypomagnesemia, concomitant use of drugs known to prolong the QT_c interval).

Falls

Risk of falls; may be due to postural and autonomic instability associated with parkinson disease. Risk may be increased due to effect of apomorphine on BP and mobility.

Hallucinations

Hallucinations reported in clinical studies.

During postmarketing experience, other new or worsening mental status and behavioral changes (e.g., paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, delirium) reported during therapy or after initiating or increasing dosage. Other antiparkinsonian agents can produce similar effects.

Use generally not advised in patients with a major psychotic disorder. Concomitant use with antipsychotic agents may exacerbate parkinsonian symptoms and decrease effectiveness of apomorphine.

Cardiovascular Effects

Risk of angina, MI, cardiac arrest, and/or sudden death. Angina and MI occurred in some patients within 2 hours of apomorphine dosing; cardiac arrest and sudden death occurred at times unrelated to dosing.

May exacerbate coronary and cerebral ischemia due to effects of apomorphine on BP. Use with caution in patients with cardiovascular and cerebrovascular disease.

If signs and symptoms of coronary or cerebral ischemia occur, reevaluate continued use of the drug.

Abuse Potential

Escalation of apomorphine dose beyond the prescribed frequency reported in patients trying to avoid all symptoms of an “off” episode. However, a withdrawal syndrome has not been observed.

There are postmarketing reports of apomorphine abuse, which consisted of patients taking increasing doses of the drug in order to achieve an euphoric state.

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., urticaria, rash, pruritus, angioedema) caused by apomorphine or the sulfite excipient reported.

The commercially available apomorphine hydrochloride injection contains sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

General Precautions

Dyskinesia

May cause or exacerbate dyskinesias.

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, uncontrolled spending, binge eating, other intense urges) and inability to control these urges reported in some patients receiving dopaminergic agents. In some cases, urges stopped when dosage was reduced or drug was discontinued.

Consider reducing dosage or discontinuing therapy if a patient develops such urges. (See Advice to Patients.)

Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (NMS; elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with abrupt withdrawal, dosage reduction, or changes in antiparkinsonian therapy.

Fibrotic Complications

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy reported in patients receiving ergot-derivative dopamine receptor agonists; presumably related to the ergoline structure of these agents. Possible that nonergot-derived drugs that increase dopaminergic activity (e.g., apomorphine) may induce similar changes.

Priapism

Possible prolonged painful erections.

Ocular Effects

Retinal degeneration reported in albino rats given dopamine agonists for prolonged periods (usually 2-year carcinogenicity studies); similar changes not observed in albino mice, rats, or monkeys. Clinical importance in humans not established; however, effect cannot be disregarded because the presumed mechanism of action may apply to all vertebrates.

Specific Populations

Pregnancy

No adequate data in pregnant women. In animal reproduction studies, increased neonatal deaths and cardiovascular malformations observed at clinically relevant doses associated with maternal toxicity.

Lactation

Not known whether apomorphine is distributed into milk. Effects on breast-fed infant or on milk production also not known. Consider known benefits of breast-feeding along with mother's clinical need for apomorphine and any potential adverse effects on the breast-fed infant from drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Increased incidence of confusion, hallucinations, serious adverse events (life-threatening events or events resulting in hospitalization and/or increased disability), falls, cardiovascular events, respiratory disorders, and GI events in geriatric individuals compared with younger adults.

Hepatic Impairment

Systemic exposure increased in patients with mild to moderate hepatic impairment; use with caution. Not studied in patients with severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment necessary in patients with mild to moderate renal impairment. Not studied in patients with severe renal impairment or those undergoing dialysis. (See Renal Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Common Adverse Effects

Yawning, dyskinesias, nausea and/or vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, pallor.

Drug Interactions

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation). (See Prolongation of QT Interval under Cautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.

Specific Drugs

Apomorphine Pharmacokinetics

Absorption

Bioavailability

Bioavailability following sub-Q administration is 100%. Peak plasma concentrations achieved in 10–60 minutes.

Onset

Following sub-Q administration, therapeutic response usually achieved in 10–20 minutes.

Duration

Approximately 60 minutes.

Special Populations

In individuals with moderate hepatic impairment receiving a single sub-Q dose of apomorphine, peak plasma concentrations and AUC were increased 25 and 10%, respectively, compared with healthy individuals.

In patients with moderate renal impairment receiving a single sub-Q dose of apomorphine, peak plasma concentrations and AUC were increased 50 and 16%, respectively, compared with healthy individuals. Time to peak plasma concentrations was not affected by renal status.

Distribution

Extent

Maximum cerebrospinal fluid concentrations are <10% of peak plasma concentrations.

Elimination

Metabolism

Routes of metabolism not known. Potential metabolic routes include sulfation, N–demethylation, glucuronidation, and oxidation.

Half-life

40 minutes.

Special Populations

Half-life not affected by renal status.

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).

Actions

• Exhibits a higher affinity for dopamine D₄ receptors in vitro than for dopamine D₂, D₃, or D₅ receptors.

• Appears to act by stimulating postsynaptic dopamine D₂ receptors in the caudate-putamen.

Advice to Patients

• Importance of taking apomorphine only as prescribed.

• Importance of instructing patient and/or caregiver regarding proper dosage and administration of apomorphine, including detailed instruction in the use of the dosing pen, in patients whose clinician has determined that the drug can safely and effectively be self-administered in the patient’s home by the patient, family member, or other responsible individual.

• Advise that hallucinations, hypotension, and other adverse effects (e.g., injection site reactions) may occur.

• Risk of orthostatic hypotension with or without dizziness, nausea, syncope, or sweating. Advise not to rise rapidly after prolonged sitting or lying down, especially during the first few weeks of therapy.

• Risk of somnolence and the possibility of falling asleep during activities of daily living; avoid driving or operating machinery until effects on the individual are known.

• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving apomorphine and advising them of the importance of reporting such urges.

• Importance of informing clinicians if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, riding in a car as a passenger) occur at any time during apomorphine therapy. Patients should not drive or participate in potentially dangerous activities until their clinician has been notified.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (especially selective 5-HT₃ receptor antagonists) and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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