Apomorphine Hydrochloride

Pronunciation: a-poe-MOR-feen HYE-droe-KLOR-ide
Class: Non ergot dopamine receptor agonist

Trade Names

Apokyn
- Injection, solution 10 mg/mL

Pharmacology

Precise mechanism of action in treatment for Parkinson disease is unknown; it is believed to be caused by stimulation of postsynaptic dopamine D ₂ –type receptors in the caudate-putamen in the brain.

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Pharmacokinetics

Absorption

Rapidly absorbed. T _max is 10 to 60 min.

Distribution

Vd is 218 L.

Metabolism

Route of metabolism is not known. Potential routes include sulfation, N-demethylation, glucuronidation, and oxidation.

Elimination

Elimination half-life is approximately 40 min. Cl is 223 L/h.

Special Populations

Renal Function Impairment

AUC and C _max were increased by 16% and 50%, respectively, in patients with moderate renal impairment. Effect of severe renal impairment has not been studied.

Hepatic Function Impairment

AUC and C _max were increased by 10% and 25%, respectively, in patients with moderate hepatic impairment. Effect of severe hepatic impairment has not been studied.

Elderly

Cl does not appear to be affected.

Gender

Cl does not appear to be affected.

Weight

Cl does not appear to be affected.

Indications and Usage

Acute, intermittent treatment of hypomobility, “off” episodes associated with Parkinson disease.

Contraindications

Concomitant use with 5-HT ₃ antagonists (eg, alosetron, dolasetron, granisetron, ondansetron, palonosetron); hypersensitivity to product or any of the components (including sodium metabisulfite).

Dosage and Administration

Parkinson Disease
Adults

Subcutaneous Titrate based on effectiveness and tolerance, starting at 0.2 mL (2 mg) and increasing up to a max recommended dose of 0.6 mL (6 mg). Usual dosage is 0.3 to 0.6 mL (3 to 6 mg). Average frequency of dosing is 3 times/day and there is limited experience with dosing more than 5 times/day and with total daily doses greater than 2 mL (20 mg).

Test dose

Subcutaneous Initially, patients in an “off” state should be given a 0.2 mL test dose in a setting in which BP can be closely monitored. If this dose is tolerated and the patient 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. For patients who tolerate this test dose 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 h after the initial test dose. If the patient tolerated the 0.4 mL (4 mg) test dose, 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 the patient does not tolerate the 0.4 mL (4 mg) dose, a test dose of 0.3 mL (3 mg) may be administered during a separate “off” period, but no sooner than 2 h after the last test dose. If the patient tolerated 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 in 0.3 mL (3 mg) after a few days. In such patients, the dose ordinarily should not be increased to 0.4 mL (4 mg) on an outpatient basis.

Renal function impairment

Subcutaneous Testing dose and starting dose should be reduced to 0.1 mL (1 mg) in mild and moderate renal impairment.

General Advice

• For subcutaneous administration only. Do not administer IV; serious adverse events (eg, IV crystallization leading to thrombus formation and pulmonary embolism) have followed the IV administration.
• The prescribed dose should always be expressed in mL to avoid confusion.
• Both supine and standing BP should be checked predose and at 20, 40, and 60 min postdose for all test doses.
• Use a concomitant antiemetic, generally trimethobenzamide 300 mg 3 times daily, starting 3 days prior to the initial dose of apomorphine and continue for at least the first 2 mo of therapy.
• Patients who have had a significant interruption in therapy (more than 1 wk) should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

The effects of apomorphine on BP may be increased, resulting in hypotension. Avoid concurrent use.

Antihypertensive agents (eg, propranolol), vasodilators (eg, nitrates)

The effects of apomorphine on BP may be increased, resulting in hypotension. Coadminister with caution. Closely monitor BP.

Dopamine antagonists (eg, butyrophenones [eg, haloperidol], phenothiazines [eg, chlorpromazine], thioxanthenes [eg, thiothixene], metoclopramide)

Because apomorphine is a dopamine agonist, dopamine antagonists may diminish the effectiveness of apomorphine. Avoid coadministration.

5-HT ₃ receptor antagonists (eg, alosetron, dolasetron, granisetron, ondansetron, palonosetron)

The risk of profound hypotension and loss of consciousness may be increased. Coadministration is contraindicated.

Levodopa

Apomorphine may decrease the threshold levodopa concentration necessary for an improved motor response, leading to an increased duration of effect without a change in maximal response to levodopa therapy. Levodopa plasma concentrations and duration of effect may be decreased if administered during the effective (“on”) period of apomorphine. Administer levodopa after the end of an apomorphine-induced “on” period.

Adverse Reactions

Cardiovascular

Chest pain/pressure/angina (15%); orthostatic hypotension/hypotension/syncope (11%); CHF (at least 5%).

CNS

Drowsiness or somnolence, dyskinesias (35%); dizziness or postural hypotension (20%); hallucination (14%); confusion (10%); aggravated Parkinson disease, anxiety, confusion, depression, fatigue, headache, insomnia, weakness (at least 5%); impulse control symptoms, increased libido (including hypersexuality), pathological gambling (postmarketing).

Dermatologic

Ecchymosis, sweating increased (at least 5%); flushing; pallor.

EENT

Rhinorrhea (20%).

GI

Nausea (31%); nausea and/or vomiting (30%); vomiting (11%); constipation, diarrhea (at least 5%).

Genitourinary

UTI (at least 5%).

Local

Injection-site reactions (26%); bruising (16%); granuloma (4%); pruritus (2%).

Musculoskeletal

Arthralgia, back pain, limb pain (at least 5%).

Respiratory

Dyspnea, pneumonia (at least 5%).

Miscellaneous

Yawning (40%); falls (30%); edema/swelling of the extremities (10%); dehydration (at least 5%).

Precautions

Monitor Carefully monitor for signs and symptoms of orthostatic hypotension, especially during dose escalation. Continually reassess patients for drowsiness or sleepiness. Monitor for melanoma frequently and on a regular basis.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Incidence of hallucinations and serious adverse reactions appears to be increased with age.

Renal Function

Dosage adjustment needed in patients with mild or moderate renal impairment; studies have not been conducted in patients with severe renal impairment.

Hepatic Function

Use with caution in patients with mild or moderate hepatic impairment; studies have not been conducted in patients with severe hepatic impairment.

Sulfite Sensitivity

May contain sodium metabisulfite. Use with caution in sulfite-sensitive patients.

Abuse potential

Abuse, characterized by increasingly frequent dosing leading to hallucinations, dyskinesias, and abnormal behaviors, has been rarely reported. Abuse has also been associated with inappropriate sexual behavior.

CNS effects

New or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior, have been reported after starting or increasing the dose of apomorphine.

Coronary events

Angina, MI, cardiac arrest, and/or sudden death have been reported during clinical development. Use with caution in patients with CV or cerebrovascular disease.

Dyskinesias

May cause dyskinesia or exacerbate preexisting dyskinesia.

Falling asleep

Falling asleep during activities of daily living has been reported. Consider discontinuation of therapy in patients who develop significant daytime sleepiness or episodes of falling asleep during activities that require active participation (eg, conversations, eating). If therapy is continued in such patients, caution patients not to drive and to avoid other potentially hazardous activities.

Falls

May increase risk of falls by lowering BP and altering mobility.

Fibrotic complications

A small number of cases of possible fibrotic complications, including cardiac valvulopathy, pleural effusion, pleural thickening, pulmonary infiltrates, and retroperitoneal fibrosis, have been reported in patients treated with ergot-derived dopaminergic agents. It is not known if nonergot-derived dopamine agonists can cause these complications.

Hallucinations

Can occur during apomorphine therapy.

Hypotension

Orthostatic hypotension may occur, especially during dose escalation.

Major psychotic disorders

Major psychotic disorders may be exacerbated.

Melanoma

Patients with Parkinson disease have a higher risk of developing melanoma than the general population.

Nausea and vomiting

Severe nausea and vomiting can be expected.

Priapism

Prolonged painful erections may occur in some patients. Severe priapism may require surgical intervention.

QT prolongation and proarrhythmia

May occur. Use with caution in patients with risk factors for QT prolongation.

Syncope

Syncope has been observed.

Withdrawal-emergent hyperpyrexia and confusion

A symptom complex resembling NMS has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

Overdosage

Symptoms

Bradycardia, hypotension, loss of consciousness, nausea.

Patient Information

• Instruct patients and caregivers to read the patient package insert and directions for use of the dosing pen.
• Advise patients that drug is intended for use by subcutaneous injection only. Instruct patients to use only as prescribed.
• Educate patients that the drug is dosed in mL, not mg. Instruct them on how to properly dial a dose.
• Inform patients and caregivers that it is possible to dial their usual dose even though the cartridge may contain less than that amount of drug. In this case, they will only receive a partial dose with the injection and the amount left to inject will appear in the dosing window. To complete the correct dose they will need to “re-arm” the device and dial in the correct amount of the remaining dose.
• Instruct patients to rotate the injection site and to use proper aseptic technique.
• Advise patient or caregiver that medication may cause postural hypotension with or without symptoms such as dizziness, fainting, nausea, and sweating, especially when therapy is first started or following a dosage increase.
• Caution patient to get up slowly from a lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Instruct patient to lie or sit down if they experience dizziness, light-headedness, and/or faintness when standing.
• Advise patient or caregiver that medication may cause hallucinations (unreal visions, sounds, or sensations) or other manifestations of psychotic-like behavior and to notify health care provider if these occur.
• Advise patient that drug may cause drowsiness and present the possibility of falling asleep while engaged in activities of daily living, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined. Instruct patient to stop driving or participating in other potentially dangerous activities and to notify health care provider if they experience increasing drowsiness or sleepiness, or episodes of falling asleep during activities of daily living.
• Instruct patient to avoid alcohol and other CNS depressant medications while taking apomorphine.
• Inform patients that there have been reports of patients experiencing intense urges to gamble, sexual urges, other intense urges, and the inability to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson disease, including apomorphine. Advise patients to inform their health care provider if they experience any new or increased urges.

Copyright © 2009 Wolters Kluwer Health.