apomorphine (Rx)

Brand and Other Names:Apokyn, Kynmobi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

solution for SC injection

  • 10mg/mL (30mg/3mL pen injector)

SL film

  • 10mg
  • 15mg
  • 20mg
  • 25mg
  • 30mg

Parkinson Disease

Indicated for acute, intermittent treatment of hypomobility, "off" episodes (end-of-dose wearing "off" and unpredictable "on-off" episodes) associated with advanced Parkinson disease

Subcutaneous (Apokyn)

  • Initial: 2 mg (0.2 mL) SC PRN
  • Also see Administration for details regarding test dose
  • Titrate on the basis of effectiveness and tolerance; not to exceed 6 mg (0.6 mL)/dose
  • Average frequency of dosing in clinical trials was TID
  • Limited experience with single doses >6 mg, dosing >5 times per day, or with total daily doses >20 mg

Sublingual (Kynmobi)

  • Initial: 10 mg SL PRN; not to exceed 5 doses/day
  • Separate doses by at least 2 hr; if a single dose is ineffective for a particular “off” episode, a second dose should not be given for that “off” episode
  • Maximum single dose: 30 mg

Premedication

  • High incidence of nausea and vomiting with treatment; initiate an antiemetic (eg, trimethobenzamide 300 mg TID) 3 days prior to the initial apomorphine dose
  • Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than 2 months after initiation of treatment
  • Trimethobenzamide increases the incidence of somnolence, dizziness, and falls
  • Contraindicated with 5HT3 antagonist antiemetics (eg, ondansetron, granisetron, dolasetron, palonosetron) owing to profound hypotension and loss of consciousness when coadministered

Dosage Modifications

Renal impairment

  • Mild-to-moderate: Reduce test dose and starting dose to 1 mg (0.1 mL); peak plasma concentration and AUC increased in these patients
  • Severe: Not studied

Hepatic impairment

  • Mild–to-moderate: Use caution; peak plasma concentration and AUC increased in these patients
  • Severe: Not studied

Vegetative State (Orphan)

Treatment of patients in a vegetative state or minimally conscious state for up to 12 months following a severe traumatic brain injury

Orphan indication sponsor

  • NeuroHealing Pharmaceuticals, Inc; 50 Undine Road; Newton, MA 02135

Acute Myeloid Leukemia (Orphan)

Orphan designation for treatment of acute myeloid leukemia (AML)

Orphan sponsor

  • Leukos Biotech; Muntaner 383, 3°2°; Barcelona, Spain

Amyotrophic Lateral Sclerosis (Orphan)

Orphan designation for treatment of amyotrophic lateral sclerosis (ALS)

Orphan sponsor

  • Aclipse One Inc; 170 North Radnor Chester Road, Suite 350; Wayne, Pennsylvania 19087

Safety and efficacy not established

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Interactions

Interaction Checker

and apomorphine

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            Adverse Effects

            >10%

            SC

            • Yawning (40%)
            • Dyskinesia (35%)
            • Drowsiness or somnolence (35%)
            • Nausea or vomiting (30%)
            • Injection site reaction (26%)
            • Dizziness or postural hypotension (20%)
            • Rhinorrhea (20%)
            • Bruising (16%)
            • Chest pain/pressure/angina (15%)

            SL

            • Nausea (21-28%)
            • Oral/pharyngeal soft tissue swelling (1-15%)
            • Somnolence (11-13%)
            • Oral/pharyngeal soft tissue pain and paresthesia (2-13%)
            • Dizziness (9-11%)

            1-10%

            SC

            • Hallucination or confusion (10%)
            • Edema/swelling of extremities (10%)
            • Granuloma (4%)
            • Pruritus (2%)

            SL

            • Headache (6-8%)
            • Rhinorrhea (6-7%)
            • Oral mucosal erythema (4-7%)
            • Vomiting (4-7%)
            • Fatigue (3-7%)
            • Oral ulceration and stomatitis (2-7%)
            • Hypersensitivity (6%)
            • Fall (4-6%)
            • Hyperhidrosis (4-6%)
            • Dry mouth (1-6%)
            • Laceration (1-6%)
            • Syncope/hypotension (2-4%)
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            Warnings

            Contraindications

            Hypersensitivity, including angioedema or anaphylaxis

            Sulfite/sulfur allergies (Apokyn contains sodium metabisulfite)

            Do not use 5-HT3 antagonists, including antiemetics (eg, granisetron, dolasetron, ondansetron, palonosetron) - risk of profound hypotension and loss of consciousness

            Cautions

            Subcutaneous use only; thrombus formation and pulmonary embolism have followed IV administration owing to crystallization of apomorphine

            Severe nausea and vomiting occurs at recommended doses; because of this, premedicate with trimethobenzamide; trimethobenzamide reduces incidence of nausea and vomiting during first 4 weeks of therapy; patients treated with trimethobenzamide experience greater incidence of somnolence, dizziness and falls; benefit of treatment with trimethobenzamide must be balanced with risk for those adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, which should generally be no longer than 2 months

            Closely monitor patients with mild and moderate hepatic impairment

            Falling asleep during activities of daily living and daytime somnolence may occur

            Oral mucosal irritaiton reported with SL product

            Syncope and hypotension/orthostatic hypotension may occur

            Falls may occur, or increase owing to underlying postural instability, possible autonomic instability, and syncope caused by low blood pressure

            May cause hallucinations and psychotic-like behavior

            May cause dyskinesia or exacerbate pre-existing dyskinesia (reported with SC administration)

            May cause problems with impulse control and impulsive behaviors; consider dose reduction or discontinuing

            Coronary events (eg, angina, MI, cardiac arrest, and/or sudden death) reported in clinical trials; apomorphine reduces resting systolic and diastolic BP and may have the potential to exacerbate ischemia

            Dose-related QT prolongation observed with therapeutic doses of SC apomorphine; although the extent of systemic exposure and peak plasma concentration of apomorphine are lower following the maximum recommended SL dose (30 mg) than following the maximum recommended dose of SC apomorphine (6 mg), QTc prolongation cannot be excluded with SL administration

            Withdrawal-emergent hyperpyrexia and confusion reported

            Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents; these complications are thought to be associated with ergoline structure dopamine agonists, whether other nonergot derived dopamine agonists (eg, apomorphine) can cause these reactions is unknown

            Hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur with SL or SC dosing; SC has sulfite excipient; sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people

            Rare incidences of priapism reported during clinical trials

            Retinal atrophy detected at all SC doses in albino rat; retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for prolonged periods (~2 years)

            Drug interaction oveview

            • 5HT3 Antagonists
              • Contraindicated with 5HT3 antagonists (eg, ondansetron, granisetron, dolasetron, palonosetron)
              • Profound hypotension and loss of consciousness observed when SC apomorphine was administered with ondansetron
            • Antihypertensives and vasodilators
              • Coadministration may decrease blood pressure
              • In a study of SC apomorphine coadministered with SL nitroglycerin, a greater decrease in blood pressure was observed than apomorphine alone
              • Advise patients to lie down before and after taking SL nitroglycerin
            • Alcohol
              • Avoid drinking alcohol after taking apomorphine
              • Coadministration may decrease blood pressure
            • Dopamine antagonists
              • Dopamine antagonists such as neuroleptics (eg, phenothiazine, butyrophenones, thioxantenes) or metoclopramide may diminish the effect of apomorphine (a dopamine agonist)
            • QT prolonging drugs
              • Caution of coadministered with other drugs that prolong QT interval

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            Pregnancy & Lactation

            Pregnancy

            Adequate data on the developmental risk associated with use of apomorphine are not available in pregnant women

            In animal reproduction studies, apomorphine had adverse developmental effects in rats (increased neonatal deaths) and rabbits (increased incidence of malformation) when administered during pregnancy at clinically relevant doses; these doses were also associated with maternal toxicity

            Lactation

            Unknown if distributed in human breast milk

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Morphine derivative; nonergoline dopamine agonist of D2-type receptors within the caudate putamen in the brain

            Absorption

            Peak plasma time

            • SC: 10-60 min
            • SL: 30-60 min

            Distribution

            Vd

            • SC: 218 L
            • SL: 3630 L

            Metabolism

            Route of metabolism is unknown; potential metabolic routes include sulfation, oxidation, glucuronidation, and N-demethylation

            Elimination

            Half-life

            • SC: 40 min
            • SL: 1.7 hr

            Clearance

            • SC: 223 L/hr
            • SL: 1440 L/hr

            Excretion

            • SC: Urine (93%); feces (16%)
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            Administration

            Initial dose and dose titrations should be performed by a healthcare provider

            Measure blood pressure and pulse in supine and standing positions before and after dosing

            SL Administration

            Must be administered whole, do not cut, chew or swallow

            Before each dose, drink water to moisten mouth to help film dissolve more easily

            Film disintegrates in ~3 minutes

            Dose titration

            • Dose initiation should occur when patient is in an “off” state and in setting where clinician can monitor blood pressure and pulse
            • Instruct patients to not take their regular morning dose of carbidopa/levodopa or any other adjunctive Parkinson disease medications, and to take their last dose of carbidopa/levodopa (or adjunctive medications) no later than midnight the night before
            • If patient tolerates 10-mg dose and responds adequately, the starting dose should be 10 mg, used prn, up to 5 times per day, to treat “off” episodes
            • Insufficient response
              • If 10-mg dose tolerated, but response is insufficient, resume patient’s usual Parkinson disease medications and up-titration with apomorphine generally within 3 days
              • Increase dosage by 5-mg increments and assess response
              • Continue titration in a similar manner, under physician supervision, until effective and tolerable dose achieved

            SC Administration

            For subcutaneous (SC) administration only; thrombus formation and pumonary embolism have followed IV administration owing to crystallization of apomorphine

            Test dose

            • Begin dosing when patients are in an “off” state
            • Initial dose should be a 2 mg test dose in a setting where medical personnel can closely monitor blood pressure and pulse; both supine and standing blood pressure and pulse should be checked predose and at 20 minutes, 40 minutes, and 60 minutes postdose (and after 60 minutes, if there is significant hypotension at 60 minutes)
            • Patients who develop clinically significant orthostatic hypotension in response to this test dose should not be considered candidates for treatment
            • If the patient tolerates the 2-mg dose, and responds adequately, the starting dose should be 2 mg, used on an as needed basis to treat recurring “off” episodes
            • If needed, the dose can be increased in 1-mg increments every few days on an outpatient basis
            • Patient tolerates 2-mg test dose but does not respond
              • 4 mg may be administered under medical supervision, at least 2 hr after initial test dose, at the next observed “off” period
              • If 4-mg test dose tolerated and patient responded, the initial maintenance dose should be 3 mg used on an as needed basis to treat recurring “off” episodes as an outpatient
              • If needed, the dose can be increased in 1-mg increments every few days on an outpatient basis
            • Patient does not tolerate 4-mg test dose
              • If 4-mg test dose not tolerated, a 3-mg test dose may be administered during a separate “off” period under medical supervision (ie, at least 2 hr after the previous dose)
              • If 3-mg test dose tolerated, the initial maintenance dose should be 2 mg used on an as needed basis to treat existing “off” episodes
              • If needed, and the 2-mg dose is tolerated, the dose can be increased to 3 mg after a few days
              • In such a patient, the dose should ordinarily not be increased to 4 mg on an outpatient basis

            Retreatment and dose interruption

            • If a single dose is ineffective for a particular “off” period, a second dose should not be given for that “off” episode
            • The efficacy of the safety of administering a second dose for a single “off” episode has not been studied systematically
            • Do not administer a repeat dose sooner than 2 hr after the last dose
            • Patients who have an interruption in therapy >1 week should be restarted on a 2-mg dose and gradually titrated to effect and tolerability

            Storage

            SC injection: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

            SL film: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F); keep in foil pouch until ready to administer

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            Formulary

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            Tier Description
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