Apomorphine Hydrochloride

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
Brands: Apokyn

Introduction

Nonergot-derivative dopamine receptor agonist.1 4

Uses for Apomorphine Hydrochloride

Hypomobility Episodes Associated with Parkinson’s Disease

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’s disease (designated an orphan drug by FDA for this use).1 2 3 4 6 5 8 9 11 12 13 14

Slideshow: Parkinson’s Disease - 10 Clinical Fast Facts

Used as an adjunct to other antiparkinsonian agents (e.g., levodopa, oral dopamine receptor agonists).1 2 5 8 11

Acute Poisoning

Formerly used to induce vomiting in the early management of acute oral drug overdose and in certain cases of oral poisoning (dose: 5–6 mg sub-Q).15

Apomorphine Hydrochloride 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.1 11

  • Avoid certain other antiemetic agents (i.e., selective 5-HT3 receptor antagonists, dopamine-receptor antagonists [metoclopramide, phenothiazines]).1 4 (See Contraindications under Cautions and Specific Drugs under Interactions.)

Administration

Sub-Q Administration

Administer by sub-Q injection using the dosing pen on an as-needed basis to reverse “off” episodes.1

Administer sub-Q injections in the abdomen, thigh, or upper arm; rotate injection sites.1

Test dose: Administer all test doses in a medical setting where BP can be closely monitored.1 Measure supine and standing BP prior to and 20, 40, and 60 minutes after each test dose.1

Test dose: Determine dose when patient is experiencing an “off” episode.1 Induction of an “off” state can be facilitated by withholding the patient’s antiparkinsonian agents overnight.1

Do not administer IV; possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism).1

Dosage

Available as apomorphine hydrochloride; dosage expressed in terms of the salt.1

Provide dosing instructions for the patient or their caregiver in mL; dose on the dosing pen device is expressed in terms of mL.1

Titrate dose according to patient’s response and tolerance.1

Adults

Hypomobility Episodes Associated with Parkinson’s Disease
Sub–Q

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

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.1

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.1 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.1 If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.1

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.1 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.1 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.1 The dose should not usually be increased to 0.4 mL (4 mg) on an outpatient basis in these patients.1

In clinical studies, most patients responded to doses of 0.3–0.6 mL (3–6 mg); average frequency of dosing was 3 times daily.1

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

Prescribing Limits

Adults

Hypomobility Episodes Associated with Parkinson’s Disease
Sub-Q

No more than one dose of apomorphine should be administered for treatment of a single “off” episode.1 Safety and efficacy of a second dose during the same hypomobility episode in patients not responding to the initial dose have not been established.1

Doses >0.6 mL (6 mg) not associated with additional therapeutic effect and are not recommended.1

Limited experience with >5 doses per day or daily dosages >2 mL (20 mg).1

Special Populations

Hepatic Impairment

No special recommendations for patients with hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

In patients with mild or moderate renal impairment, initial test dose and subsequent starting dose is 0.1 mg (1 mg).1

Cautions for Apomorphine Hydrochloride

Contraindications

  • Concomitant use with selective 5-HT3 receptor antagonists.1 (See Specific Drugs under Interactions.)

  • Known hypersensitivity to apomorphine hydrochloride or any ingredient in the formulation (e.g., sodium metabisulfite).1

Warnings/Precautions

Warnings

Administration

Thrombus formation and pulmonary embolism reported following IV administration.1 14 Do not administer IV.1

Nausea and Vomiting

Severe nausea and vomiting expected; concomitant use of an antiemetic recommended.1 Trimethobenzamide was used in clinical studies; other antiemetics are contraindicated (i.e., 5-HT3 receptor antagonists) or not recommended (i.e., dopamine-receptor antagonists).1 (See General under Dosage and Administration and Specific Drugs under Interactions.)

Symptomatic Hypotension

Risk of orthostatic hypotension, hypotension, and/or syncope.1

Whether hypotension contributes to other adverse events (e.g., falls) unknown.1

Prolongation of QT Interval

Possible prolonged QT interval.1 Doses of ≤6 mg are associated with minimal increases in QTc interval.1

Use with caution in patients with congenital or known QT interval prolongation, in those with clinically important bradycardia, in those with uncorrected electrolyte disorders (e.g., hypokalemia, hypomagnesemia), and in those receiving drugs known to prolong the QTc interval.1

Nervous System and Muscular Effects

Risk of falls; may be due to postural and autonomic instability associated with Parkinson’s disease.1 Risk may be increased due to effect of apomorphine on BP and mobility.1

Symptom complex resembling neuroleptic malignant syndrome reported in association with abrupt withdrawal, dosage lowering, or changes in antiparkinsonian therapy.1

Hallucinations

Potential for hallucinations.1

Sudden Sleep Episodes

Falling asleep while engaged in activities of daily living has been reported in patients receiving apomorphine.1 While somnolence occurs frequently in patients receiving apomorphine, these patients perceived no warning signs and believed they were alert immediately prior to the event.1 Many experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.1

Continually reassess patients for drowsiness or sleepiness.1 Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1 Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, the presence of sleep disorders).1

Apomorphine generally should be discontinued if a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).1 If the drug is continued, the patients should be advised not to drive and to avoid other potentially dangerous activities.1 Insufficient information to establish whether dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.1

Cardiovascular Effects

Risk of angina, MI, cardiac arrest, and/or sudden death.1 Angina and MI occurred in some patients within 2 hours of apomorphine dosing; cardiac arrest and sudden death occurred at times unrelated to dosing.1

May exacerbate coronary and cerebral ischemia due to effects of apomorphine on BP.1 Use with caution in patients with cardiovascular and cerebrovascular disease.1

If signs and symptoms of coronary or cerebral ischemia occur, reevaluate continued use of the drug.1

Injection Site Reactions

Injection site reactions (bruising, granuloma, pruritus) reported.1

Abuse and Misuse Potential

Escalation of apomorphine dose beyond the prescribed frequency reported in patients trying to avoid all symptoms of an “off” episode.1 Hypersexuality and increased erections can occur due to abuse of apomorphine.1 11

Monitor patients for excessive use (e.g., use out of proportion to motor signs).1

Sensitivity Reactions

Sulfite Sensitivity

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.1

General Precautions

Dyskinesia

May cause or exacerbate dyskinesias.1

Cardiorespiratory Fibrosis and 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.1 Possible that nonergot-derived drugs that increase dopaminergic activity (e.g., apomorphine) may induce similar changes.1

Priapism

Possible prolonged painful erections.1

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.1 Clinical importance in humans not established; however, effect cannot be disregarded because the presumed mechanism of action may apply to all vertebrates.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether apomorphine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy for hypermobility episodes not established.1

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.1

Hepatic Impairment

Systemic exposure increased in patients with mild to moderate hepatic impairment; use with caution.1 Not studied in patients with severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment necessary in patients with mild to moderate renal impairment.1 Not studied in patients with severe renal impairment or those undergoing dialysis.1 13 (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, and pallor.1

Interactions for Apomorphine Hydrochloride

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation).1 (See Prolongation of QT Interval under Cautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Antihypertensive agents and vasodilators

Potential pharmacologic interaction (additive hypotensive effects)1

Concomitant use associated with increased incidence of hypotension, MI, pneumonia, serious falls, bone and joint injuries1

Caution1

Catecho-O-methyltransferase (COMT) inhibitors

Pharmacokinetic interaction unlikely1 7

CNS depressants

Alcohol: Potential pharmacologic interaction (additive sedative and hypotensive effects)1

CNS depressants: Potential pharmacologic interaction (additive sedative effects)1

5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)

Potential pharmacologic interaction (profound hypotension and loss of consciousness)1

Concomitant use contraindicated1

Dopamine-receptor antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide)

Potential pharmacologic interaction (reduced efficacy of apomorphine)1

Phenothiazines, butyrophenones, thioxanthenes: Weigh benefits and risks of therapy with a dopamine agonist in patients receiving one of these dopamine-receptor antagonists for the treatment of major psychosis1

Levodopa/carbidopa

Potential pharmacologic interaction (additive neurologic effect; used to therapeutic effect)1

Pharmacokinetic interaction unlikely1

Apomorphine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Bioavailability following sub-Q administration is 100%.1 Peak plasma concentrations achieved in 10–60 minutes.1

Onset

Following sub-Q administration, therapeutic response usually achieved in 10–20 minutes.1 2 5 8 12

Duration

Approximately 60 minutes.1 2 5 8 12

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.1

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.1 Time to peak plasma concentrations was not affected by renal status.1

Distribution

Extent

Maximum cerebrospinal fluid concentrations are <10% of peak plasma concentrations.1

Elimination

Metabolism

Routes of metabolism not known.1 Potential metabolic routes include sulfation, N–demethylation, glucuronidation, and oxidation.1

Half-life

40 minutes.1

Special Populations

Half-life not affected by renal status.1

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).1

Actions

  • Exhibits a higher affinity for dopamine D4 receptors in vitro than for dopamine D2, D3, or D5 receptors.1

  • Appears to act by stimulating postsynaptic dopamine D2 receptors in the caudate-putamen.1

Advice to Patients

  • Importance of taking apomorphine only as prescribed.1

  • 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.1

  • Advise that hallucinations, hypotension, and other adverse effects (e.g., injection site reactions) may occur.1

  • Risk of orthostatic hypotension with or without dizziness, nausea, syncope, or sweating.1 Advise not to rise rapidly after prolonged sitting or lying down, especially during the first few weeks of therapy.1

  • 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.1

  • 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.1 Patients should not drive or participate in potentially dangerous activities until their clinician has been notified.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Apomorphine Hydrochloride (Hemihydrate)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for sub-Q use only

10 mg/mL

Apokyn (with sodium metabisulfite; benzyl alcohol 0.5% in cartridges)

Mylan

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) injection prescribing information. Research Triangle Park, NC; 2004 Apr.

2. Stacy M. Apomorphine: North American clinical experience. Neurology. 2004; 62 (Suppl 4):S18-21. [IDIS 516185] [PubMed 15037667]

3. Dewey RB Jr. Management of motor complications in Parkinson’s disease. Neurology. 2004; 62 (Suppl 4):S3-7. [IDIS 516182] [PubMed 15037664]

4. Anon. FDA approves Apokyn for the acute treatment of episodes of immobility in Parkinson’s patients. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2004 Apr 21.

5. Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001; 58:1385-92. [IDIS 518541] [PubMed 11559309]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website (). Accessed 2004 Aug 16.

7. Zijlmans JCM, Debilly B, Rascol O et. al. Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson’s disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study. Mov Disord. 2004; 19:1006-11. [PubMed 15372589]

8. Sherry JH, Guyton PJ, Van Lunen B, Bottini PB. Continued efficacy and safety of subcutaneous injections of apomorphine in the treatment of off episodes in patients with Parkinson’s disease. Neurology. 2003; 60 (Suppl 1): A81.

9. Hughes AJ, Bishop S, Kleedorfer B et al. Subcutaneous apomorphine in Parkinson’s disease: response to chronic administration for up to five years. Mov Disord. 1993; 8:165-70. [PubMed 8474483]

10. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use: warning statement. [Docket No. 84N-0113] Fed Regist. 1985; 50:47558-63.

11. Anon. Apomorphine (Apokyn) for advanced Parkinson’s disease. Med Lett Drugs Ther. 2005; 47:7-8.

12. Factor SA. Literature review: intermittent subcutaneous apomorphine therapy in Parkinson’s disease. Neurology. 2004; 62(Suppl 4):S12-7. [IDIS 516184] [PubMed 15037666]

13. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) monograph. Research Triangle Park, NC; 2004 May 26.

14. Koller W, Stacy M. Other formulations and future considerations for apomorphine for subcutaneous injection therapy. Neurology. 2004; 62(Suppl 4):S22-6. [IDIS 516186] [PubMed 15037668]

15. AHFS Drug Information 1990. McEvoy, GK, ed. Apomorphine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 1990:1652-3.

16. Mylan Bertek Pharmaceuticals, Overland Park, KS: Personal communication.

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