Apomorphine drug Uses, dosage and side effects

Description of Apomorphine

Apomorphine, a non-narcotic derivative of morphine, is approved as a sublingual film for the treatment of acute, intermittent ‘off’ episodes associated with Parkinson’s disease and as a subcutaneous injection for use in patients with advanced Parkinson’s disease. Apomorphine has also been used as a diagnostic test for dopaminergic responsiveness in parkinsonian syndromes to determine whether a patient will respond or is still responsive to levodopa therapy. Apomorphine has a quick onset of action, a significant effect on parkinsonian hypomobility (‘off’ episodes) unresponsive to oral medications, and a therapeutic effect comparable to levodopa. Due to a high incidence of nausea and vomiting, apomorphine is coadministered with the antiemetic drug trimethobenzamide. Based on reports of profound low blood pressure and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of 5-HT3 antagonists with apomorphine is contraindicated. Similar to other dopamine agonists, apomorphine has been associated with sudden sleep onset during activities of daily living and impulse control symptoms (e.g., intense urges to gamble or spend money, increased sexual urges). During treatment with apomorphine, practitioners should monitor for hypotension, orthostasis, new or worsening impulse control symptoms, and patient reports of sudden sleep onset.

Mechanism of Action of Apomorphine

Apomorphine has structural similarities to the neurotransmitter dopamine that are thought to contribute to its central dopamine receptor agonist properties. Apomorphine exhibits a high affinity for dopamine D4 receptors, a moderate affinity for dopamine D2, D3, and D5 receptors, and a low affinity for D1 receptors. Apomorphine may be a partial agonist at D1 receptors; however, further studies are needed to confirm this effect. Although the exact mechanism by which apomorphine exerts its therapeutic effects in Parkinson’s disease is unknown, it is thought to occur via activation at postsynaptic D2 receptors in the caudate nucleus and putamen. Apomorphine has a moderate affinity for alpha-1D, alpha-2B, and alpha-2C adrenergic receptors, and a low affinity for the serotonin receptors 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C. Stimulation of the chemoreceptor trigger zone (CTZ) by the drug produces potent emetic actions. Apomorphine is a morphine derivative, but generally does not possess any narcotic effects, with the exception of emesis induction, CNS depression, and respiratory depression.

Pharmacokinetics of Apomorphine

Apomorphine is administered by subcutaneous injection or sublingual film. A high first-pass metabolism prohibits the use of an oral formulation. Apomorphine has a large volume of distribution and is 85% to 90% bound to plasma proteins, predominantly to albumin. Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes after maximum plasma concentrations are achieved from subcutaneous dosing. Metabolism is thought to occur in the liver through several pathways including glucuronidation, sulfation, and N-demethylation. Apomorphine does not appear to be significantly metabolized by catechol-O-methyl transferase (COMT). The primary metabolite, apomorphine sulfate, is not pharmacologically active. N-demethylation produces norapomorphine. This metabolite is thought to possess some pharmacologic activity, but it has a lower affinity for dopamine receptors than the parent compound. Several CYP450 isoenzymes are thought to be involved in the demethylation of apomorphine including CYP2B6, CYP3A4/5, and CYP2C8, but these appear to have a very minor role in the metabolism of the drug according to in vitro studies. Subcutaneous apomorphine has a mean elimination half-life of about 40 minutes (range: 30 to 60 minutes). Sublingual apomorphine has a mean elimination half-life of about 1.7 hours (range: 0.8 hours to 3 hours). The apparent clearance of apomorphine does not appear to be influenced by the duration of Parkinson’s disease, levodopa dose, use of antiemetic, or duration of therapy.

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
CYP2B6, CYP3A4/5, and CYP2C8 are thought to be involved in the demethylation of apomorphine, but these isoenzymes appear to have a very minor role in the metabolism of the drug. In vitro studies indicate that apomorphine is unlikely to act as a CYP inhibitor or inducer.

•Route-Specific Pharmacokinetics
Subcutaneous Route
The absorption of apomorphine after subcutaneous injection is dependent on many variables such as location of injection, body temperature, and percentage of body fat. Abdominal injections result in faster absorption than injections into the thigh, and lowering the temperature of the injection site slows absorption. Improvement in Parkinson’s symptoms become evident within about 7 to 14 minutes following a subcutaneous injection, with a duration of action up to 2 hours. Onset of emesis occurs within 3 to 10 minutes of a subcutaneous dose, with a duration of 60 minutes.

Inhalation Route
Intranasal Administration
Alternative formulations (e.g., intranasal inhalation) of apomorphine have been investigated as potential delivery systems but are not FDA-approved. Optimal dosages for intranasal apomorphine range from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and a duration of action ranging from 45 to 55 minutes. Side effects have included nasal irritation, vestibulitis, dyskinesias, yawning, and nausea.

Other Route(s)
Sublingual Administration (e.g., Kynmobi sublingual film)
Following sublingual administration of 15 mg of apomorphine, the time to maximum concentration (Tmax) ranged from 0.5 to 1 hour. Apomorphine exhibits less than a dose-proportional increase in exposures over a dose range of 10 mg to 35 mg (1.2 times the highest recommended dosage) following a single sublingual dose of apomorphine in patients with Parkinson’s disease.

Rectal Administration
Alternative formulations (e.g., rectal) of apomorphine have been investigated as potential delivery systems, but are not FDA-approved. Rectal administration of apomorphine has been evaluated in limited, usually post-operative settings. Administration of a 200 mg apomorphine rectal suppository resulted in an average time to benefit of 32 minutes with an average duration of action of 195 minutes. Sedation, nausea, and faintness were reported as side effects.

• Apomorphine Hydrochloride

• Apokyn
• Kynmobi

• Antiparkinsonian
• Dopamine Agonist

• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: Adult: yes ((sublingual film and subQ injection))

• Cardiovascular: Peripheral edema (10% )
• Dermatologic: Contusion (SubQ route, 16% ), Injection site disorder (5% or greater )
• Gastrointestinal: Nausea (21% to 31% ), Nausea and vomiting (30% ), Pain of oral cavity structure, and paresthesia (SL route, 2% to 13% ), Swelling of oral cavity structure (SL route, 1% to 15% ), Vomiting (4% to 11% )
• Neurologic: Confusion (5% or greater ), Dizziness (SL route, 11% ), Dyskinesia (SubQ route, 24% to 35% ), Falling injury (4% or greater )
• Psychiatric: Hallucinations (14% )
• Respiratory: Nasal discharge (SL route, 6% ; subQ route, 20% ), Yawning (SubQ route, 40% )

• Cardiovascular: Angina pectoris, Cardiac arrest, Hypotension, Myocardial infarction, Orthostatic hypotension, Prolonged QT interval, Sudden cardiac death, Syncope (2% )
• Hematologic: Hemolytic anemia
• Immunologic: Hypersensitivity reaction (SL route, up to 6% )
• Neurologic: Somnolence (SL route, 11% to 13% ; subQ route, 35% )
• Reproductive: Priapism (SubQ route, 0.8% )

• NIOSH Group 2 Non-antineoplastics
• NIOSH: In the preparation and administration of injections, use double gloves and a protective gown. Prepare in a biological safety cabinet or a compounding aseptic containment isolator; eye/face and respiratory protection may be needed. Prepare compounds in a closed system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye/face protection. Administer certain dosage forms via a closed system drug transfer device .
• Subcutaneous: Should not be initiated without use of a concomitant antiemetic
• Subcutaneous: For subQ use only; do not use IV, may lead to crystallization and thrombus formation
• Subcutaneous: Rotate injection site
• Sublingual: Initiation should be supervised by a healthcare provider .
• Sublingual: Apomorphine hydrochloride sublingual film must be administered whole; do not cute, chew, or swallow. Film will disintegrate in about 3 minutes .
• Sublingual: Doses should be separated by at least 2 hours .

• Apokyn: Subcutaneous Solution: 10 MG/1 ML
• Kynmobi: Sublingual Film: 10 MG, 15 MG, 20 MG, 25 MG, 30 MG

• Subcutaneous Solution: 10 MG/1 ML

• Important Note: To avoid confusion, the prescribed dose should be expressed in mL because the subQ pen has markings in mL .
• Important Note: Orphan drug designation: Treatment of the on-off fluctuations associated with late-stage Parkinson disease
• Important Note: Orphan drug designation: Treatment of patients in a vegetative state or minimally conscious state for up to 12 months following a severe traumatic brain injury (traumatic or spontaneous)
• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: Premedication, trimethobenzamide 300 mg orally 3 times daily beginning 3 days prior to apomorphine initiation; continue only as long as needed for control of nausea and vomiting, generally not longer than 2 months (note, concomitant use with 5HT3 antagonists [eg, ondansetron, granisetron, dolasetron, palonosetron, and alosetron] is contraindicated)
• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: (Apokyn(R)) Test dose, in an “off” state and under medical supervision (supine and standing blood pressures pre-dose, 20-, 40-, and 60-minutes post-dose): Administer 1 mg/0.1 mL subQ, and if tolerated but not effective, may give 2 mg/0.2 mL at least 2 hours after the initial test dose, at next observed “off” period. If significant orthostatic hypotension occurs with 1 mg/0.1 mL or 2 mg/0.2 mL test dose, do not proceed with use; if 2 mg/0.2 mL is not tolerated, slow titration may be needed. If 2 mg/0.2 mL is tolerated but not effective, administer a 4 mg/0.4 mL test dose at the next observed “off” episode (at least 2 hours after the initial test); if 4 mg/0.4 mL is not tolerated, may give a 3 mg/0.3 mL test dose during a separate “off” period under medical supervision, at least 2 hours after the previous dose .
• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: (Apokyn(R)) Initial dose should be the same as the test dose, 1 mg/0.1 mL to 2 mg/0.2 mL subQ. Maintenance, if 2 mg/0.2 mL test dose is tolerated, can increase to 3 mg/0.3 mL after a few days and generally not be increased to 4 mg/0.4 mL on an outpatient basis; if 3 mg/0.3 mL test dose is tolerated, maintenance dose should be 0.2 mL (2 mg); if a 4 mg/0.4 mL test dose is tolerated and effective, maintenance dose should be 0.3 mL (3 mg); dose can be increased in 0.1-mL (1-mg) increments every few days on an outpatient basis if necessary to MAX, 6 mg/0.6 mL/dose and 1 dose/episode; usual frequency is 3 times daily; there is limited experience with single doses greater than 6 mg/0.6 mL, dosing more than 5 times/day, or total daily doses greater than 20 mg/2 mL. Retreatment, if single dose is ineffective for an “off” period, wait at least 2 hours to repeat the dose; do not give a second dose for a single “off” period .
• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: (Apokyn(R)) Interruption of therapy longer than 1 week, restart with initial dose, 2 mg/0.2 mL, and titrate gradually to effect and tolerability
• Parkinson’s disease, Acute, intermittent treatment of hypomobility “off” episodes: (Kynmobi(TM)) Initial, 10 mg sublingually during “off” state as needed; if adequate response, 10 mg should be used; if response is insufficient resume usual Parkinson disease medications and titrate generally within 3 days in 5-mg increments until adequate response; doses should be separated by 2 hours; if a single dose is ineffective for a particular “off” episode, a second dose should not be given for that “off” episode; MAX, 30 mg/dose and 5 doses/da