Apomorphine Hydrochloride

Q: Is Apomorphine Hydrochloride available over the counter?

Apomorphine Hydrochloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Brand names: apomorphine hydrocloride

Dosage Form

Injection

Route

SUBCUTANEOUS

Manufacturer

TRUPHARMA, LLC

About This Medication

11 DESCRIPTION apomorphine hydrocloride (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C 17 H 17 NO 2 ∙ HCl ∙ ½ H 2 O. Its structural formula and molecular weight are: Figure 1: Structural Formula and Molecular Weight of Apomorphine M.W. 312.79 Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white powder that is soluble in water at 80°C. Apomorphine hydrocloride is a clear, colorless, sterile solution for subcutaneous injection and is available in 3 mL (30 mg) multi-dose cartridges. Each mL of solution contains 10 mg of apomorphine hydrochloride, USP as apomorphine hydrochloride hemihydrate (equivalent to 8.55 mg apomorphine), 1 mg of sodium metabisulfite, NF and 5 mg of benzyl alcohol, NF (preservative) in water for injection, USP. In addition, each mL of solution may contain sodium hydroxide, NF and/or hydrochloric acid, NF to adjust the pH of the solution. Figure 1

Active Ingredients

Ingredient	Strength
Apomorphine Hydrochloride	-

Indications & Usage

1 INDICATIONS AND USAGE Apomorphine hydrochloride injection is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) in patients with advanced Parkinson's disease. Apomorphine hydrocloride inejction has been studied as an adjunct to other medications [see Clinical Studies (14) ] . Apomorphine hydrocloride injection is a non-ergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced Parkinson's disease ( 1 )

How It Works

12.1 Mechanism of Action Apomorphine hydrocloride is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D 4 receptor, and moderate affinity for the dopamine D 2 , D 3 , and D 5 , and adrenergic α 1 D, α 2 B, α 2 C receptors. The precise mechanism of action of apomorphine hydrocloride as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D 2 -type receptors within the caudate-putamen in the brain.

Dosage & Administration

2 DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) Always express apomorphine hydrocloride dose in mL to minimize dosing errors ( 2.1 ) The starting dose of apomorphine hydrocloride is 0.2 mL (2 mg); give the first dose under medical supervision; titrate the dose to effect and tolerance; the maximum recommended dose is 0.6 mL ( 2.3 ) Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is recommended, starting 3 days prior to the first dose of apomorphine hydrocloride. Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months ( 2.2 , 5.2 , 6.1 , 17 ) Apomorphine hydrocloride doses must be separated by at least 2 hours ( 2.5 ) Renal impairment: reduce test dose, and reduce starting dose to 0.1 mL (1 mg) ( 2.4 , 8.6 , 12.3 ) 2.1 Important Administration Instructions Apomorphine hydrocloride is indicated for subcutaneous administration only [see Warnings and Precautions (5.1) ] and only by a multiple-dose APOKYN ® Pen with supplied cartridges. The APOKYN ® Pen is supplied separately by a different manufacturer. The initial dose and dose titrations should be performed by a healthcare provider. Blood pressure and pulse should be measured in the supine and standing position before and after dosing. A caregiver or patient may administer apomorphine hydrocloride if a healthcare provider determines that it is appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. Because the APOKYN ® Pen has markings in milliliters (mL), the prescribed dose of apomorphine hydrocloride should be expressed in mL to avoid confusion. Visually inspect the apomorphine hydrocloride drug product through the viewing window for particulate matter and discoloration prior to administration. The solution should not be used if discolored (it should be colorless), or cloudy, or if foreign particles are present. Rotate the injection site and use proper aseptic technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17) ] . 2.2 Premedication and Concomitant Medication Because of the high incidence of nausea and vomiting with apomorphine hydrocloride treatment, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of apomorphine hydrocloride [see Warnings and Precautions (5.2) ]. Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with apomorphine hydrocloride, as trimethobenzamide increases the incidence of somnolence, dizziness and falls in patients treated with apomorphine hydrocloride [see Warnings and Precautions (5.2) ] . Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT 3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated [see Contraindications (4) ]. 2.3 Dosing Information The recommended starting dose of apomorphine hydrocloride is 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) [see Clinical Studies (14) ] . There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg). Begin dosing when patients are in an "off" state. The initial dose should be a 0.2 mL (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 pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (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 of apomorphine hydrocloride should not be considered candidates for treatment with apomorphine hydrocloride. If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), used on an as needed basis to treat recurring "off" episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis. The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose. If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, at the next observed "off" period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring "off" episodes as an outpatient. 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 a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate "off" period under medical supervision, at least 2 hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance 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 to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis. 2.4 Dosing in Patients with Renal Impairment For patients with mild and moderate renal impairment, the test dose and starting dose should be reduced to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ] . 2.5 Re-treatment and Interruption in Therapy If a single dose of apomorphine hydrocloride 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 of apomorphine hydrocloride sooner than 2 hours after the last dose. Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect and tolerability.

Side Effects Overview

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling: Serious Adverse Reactions After Intravenous Administration [see Warnings and Precautions (5.1) ] Nausea and Vomiting [see Warnings and Precautions (5.2) ] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3) ] Syncope/Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4) ] Falls [see Warnings and Precautions (5.5) ] Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.6) ] Dyskinesias [see Warnings and Precautions (5.7) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.8) ] Coronary Events [see Warnings and Precautions (5.9) ] QTc Prolongation and Potential for Proarrhythymic Effects [see Warnings and Precautions (5.10) ] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.11) ] Hypersensitivity [see Warnings and Precautions (5.12) ] Fibrotic Complications [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence at least 10% greater on apomorphine hydrocloride than on placebo) were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice. In placebo-controlled trials, most patients received only one subcutaneous dose of apomorphine hydrocloride. All patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients had some degree of spontaneously occurring periods of hypomobility ("off episodes") at baseline. The most common adverse reactions (apomorphine hydrocloride incidence at least 10% greater than placebo incidence) observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities. Table 1 presents the most common adverse reactions reported by apomorphine hydrocloride-naïve Parkinson's disease patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were treated for up to 4 weeks (Study 1) [see Clinical Studies (14) ] . Individual apomorphine hydrocloride doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms. Table 1: Adverse Reactions Occurring in Two or More Apomorphine Hydrocloride-Treated Patients in Study 1 Apomorphine Hydrocloride (n = 20) PLACEBO (n = 9) % % Yawning 40 0 Dyskinesias 35 11 Drowsiness or Somnolence 35 0 Nausea and/or Vomiting 30 11 Dizziness or Postural Hypotension 20 0 Rhinorrhea 20 0 Chest Pain/Pressure/Angina 15 11 Hallucination or Confusion 10 0 Edema/Swelling of Extremities 10 0 Other Adverse Reactions Injection Site Reactions Patients treated with apomorphine hydrocloride subcutaneous injections during clinical studies, 26% of patients had injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). In addition to those in Table 1, the most common adverse reactions in pooled apomorphine hydrocloride trials (occurring in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, Parkinson's disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.

Warnings & Precautions

5 WARNINGS AND PRECAUTIONS For subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of apomorphine hydrocloride ( 5.1 ) Falling asleep during activities of daily living, and daytime somnolence may occur ( 5.3 ) Syncope and hypotension/orthostatic hypotension may occur ( 5.4 ) Falls may occur, or increase ( 5.5 ) May cause hallucinations and psychotic-like behavior ( 5.6 ) May cause dyskinesia or exacerbate pre-existing dyskinesia ( 5.7 ) May cause problems with impulse control and impulsive behaviors ( 5.8 ) May cause coronary events ( 5.9 ) May prolong QTc and cause torsades de pointes or sudden death ( 5.10 ) 5.1 Serious Adverse Reactions After Intravenous Administration Following intravenous administration of apomorphine hydrocloride, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, apomorphine hydrocloride should not be administered intravenously. 5.2 Nausea and Vomiting Apomorphine hydrocloride causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the apomorphine hydrocloride-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued apomorphine hydrocloride due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine hydrocloride. The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years). The effect of trimethobenzamide on reducing nausea and vomiting during treatment with apomorphine hydrocloride was evaluated in a 12-week, placebo-controlled study in 194 patients. The study suggests that trimethobenzamide reduces the incidence of nausea and vomiting during the first 4 weeks of apomorphine hydrocloride treatment (incidence of nausea and vomiting 43% on trimethobenzamide vs. 59% on placebo). However, over the 12-week period, compared with placebo, patients treated with trimethobenzamide had a greater incidence of somnolence (19% for trimethobenzamide vs. 12% for placebo), dizziness (14% for trimethobenzamide vs. 8% for placebo), and falls (8% for trimethobenzamide vs. 1% for placebo). Therefore, the benefit of treatment with trimethobenzamide must be balanced with the risk for those adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months. The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided. 5.3 Falling Asleep During Activities of Daily Living and Somnolence There have been reports in the literature of patients treated with apomorphine hydrocloride subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with apomorphine hydrocloride, and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Somnolence was reported in 35% of patients treated with apomorphine hydrocloride and in none of the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with apomorphine hydrocloride, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with apomorphine hydrocloride, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.), apomorphine hydrocloride should ordinarily be discontinued. If a decision is made to continue apomorphine hydrocloride, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.4 Syncope/Hypotension/Orthostatic Hypotension In clinical studies, approximately 2% of apomorphine hydrochloride-treated patients experienced syncope. Dopamine agonists, including apomorphine hydrochloride, may cause orthostatic hypotension at any time but especially during dose escalation. Patients with Parkinson's disease may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. Patients undergoing titration of apomorphine hydrochloride showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (≥ 20 mmHg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension (≥ 30 mm Hg decrease and systolic BP ≤ 90 mmHg) after subcutaneous apomorphine injection. In clinical trials of apomorphine hydrochloride in patients with advanced Parkinson's disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (< 1%) and resulted in withdrawal of apomorphine hydrochloride in 10 patients (2%). These events occurred both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other significant adverse events seen (e.g., falls), is unknown. Apomorphine hydrochloride causes dose-related decreases in systolic (SBP) and diastolic blood pressure (DBP) [see Clinical Pharmacology ( 12.2 )]. In a study of healthy subjects, the hypotensive effect of apomorphine hydrochloride on systolic and diastolic blood pressure) was exacerbated by the concomitant use of alcohol or sublingual nitroglycerin (0.4 mg). Patients should avoid alcohol when using apomorphine hydrochloride [see Drug Interactions ( 7.3 )]. Patients taking apomorphine hydrochloride should lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensives may also increase the hypotensive effects of apomorphine hydrochloride. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking apomorphine hydrochloride with concomitant antihypertensive medications or vasodilators [see Drug Interactions ( 7.2 , 7.3 )]. 5.5 Falls Patients with Parkinson's disease (PD) are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Subcutaneous apomorphine hydrocloride might increase the risk of falling by simultaneously lowering blood pressure and altering mobility [see Clinical Pharmacology (12.2) ] . In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of patients had falls that were considered serious. 5.6 Hallucinations / Psychotic-Like Behavior In clinical studies, hallucinations were reported by 14% of the apomorphine hydrocloride-treated patients. In one randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of patients treated with apomorphine hydrocloride and 0% of patients treated with placebo. Hallucinations resulted in discontinuation of apomorphine hydrocloride in 1% of patients. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of apomorphine hydrocloride. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with apomorphine hydrocloride because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of apomorphine hydrocloride [see Drug Interactions (7.3) ] . 5.7 Dyskinesias Apomorphine hydrocloride may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or worsening of dyskinesia was reported in 24% of patients. Overall, 2% of apomorphine hydrocloride-treated patients withdrew from studies due to dyskinesias. 5.8 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking one or more of the medications, including apomorphine hydrocloride, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with apomorphine hydrocloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking apomorphine hydrocloride. 5.9 Coronary Events In clinical studies, 4% of patients treated with apomorphine hydrocloride experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to apomorphine hydrocloride dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. apomorphine hydrocloride has been shown to reduce resting systolic and diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of apomorphine hydrocloride. 5.10 QTc Prolongation and Potential for Proarrhythymic Effects There is a dose related prolongation of QTc interval after apomorphine exposure similar to that achieved with therapeutic doses of apomorphine hydrocloride [see Clinical Pharmacology (12.2) ] . Doses greater than 6 mg do not provide additional clinical benefit and are not recommended. Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of apomorphine hydrocloride at recommended doses in clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. The risks and benefits of apomorphine hydrocloride treatment should be considered prior to initiating treatment with apomorphine hydrocloride in patients with risk factors for prolonged QTc. 5.11 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. 5.12 Hypersensitivity Hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of apomorphine hydrocloride or because of its sulfite excipient. apomorphine hydrocloride contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.13 Fibrotic Complications 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. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, whether other, nonergot derived dopamine agonists, such as apomorphine hydrocloride, can cause these reactions is unknown. 5.14 Priapism apomorphine hydrocloride may cause prolonged painful erections in some patients. In clinical studies, painful erections were reported by 3 of 361 apomorphine hydrocloride-treated men, and one patient withdrew from apomorphine hydrocloride therapy because of priapism. Although no patients in the clinical studies required surgical intervention, severe priapism may require surgical intervention. 5.15 Retinal Pathology in Albino Rats In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less than the maximum recommended human dose of 20 mg/day on a body surface area [mg/m 2 ] basis). Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies). Retinal findings were not observed in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a dose similar to the MRHD on a mg/m 2 basis. The clinical significance of the finding in rat has not been established but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.

Contraindications

4 CONTRAINDICATIONS Apomorphine hydrocloride is contraindicated in patients: Using concomitant drugs of the 5HT 3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1) ] . There have been reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron. With hypersensitivity/allergic reaction to apomorphine or to any of the excipients of apomorphine hydrocloride, including a sulfite (i.e., sodium metabisulfite). Angioedema or anaphylaxis may occur [see Warnings and Precautions (5.12) ]. Concomitant use of apomorphine hydrocloride with 5HT 3 antagonists, including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated ( 4 ) Hypersensitivity to apomorphine, its excipients or sodium metabisulfite ( 4 , 5.12 )

Pharmacokinetics

12.3 Pharmacokinetics Absorption Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 mg to 8 mg following a single subcutaneous injection of apomorphine hydrocloride into the abdominal wall in patients with idiopathic Parkinson's disease. Distribution The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later. Metabolism and Elimination The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes). The route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro , apomorphine undergoes rapid autooxidation. Specific Populations The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of Parkinson's disease, levodopa dose, or duration of therapy. Renal Impairment In a study comparing renally-impaired subjects (moderately impaired as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC 0 -∞ and C max values were increased by approximately 16% and 50%, respectively, following a single subcutaneous administration of apomorphine hydrocloride into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal impairment have not been conducted. The starting dose for patients with mild or moderate renal impairment should be reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] . Hepatic Impairment In a study comparing subjects with hepatic impairment (moderately impaired as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC 0 -∞ and C max values were increased by approximately 10% and 25%, respectively, following a single subcutaneous administration of apomorphine hydrocloride into the abdominal wall. Studies in subjects with severe hepatic impairment have not been conducted [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Drug Interaction Studies Carbidopa/levodopa Levodopa pharmacokinetics were unchanged when subcutaneous apomorphine hydrocloride and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy. Ethanol and Nitroglycerin Co-administration of low dose ethanol (0.3 g/kg) or nitroglycerin (0.4 mg) with apomorphine hydrocloride in healthy subjects did not have a significant impact on the pharmacokinetics of apomorphine, but high dose ethanol (0.6 g/kg), equivalent to approximately 3 standardized alcohol-containing beverages, increased the C max of apomorphine by about 63%. However, the hypotensive effect of apomorphine hydrocloride was increased by the concomitant use of alcohol or of sublingual nitroglycerin [see Warnings and Precautions (5.4) and Drug Interactions (7.2 , 7.3) ]. Other Drugs Eliminated Via Hepatic Metabolism Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes. COMT Interactions A pharmacokinetic interaction of apomorphine hydrocloride with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

Frequently Asked Questions

1 INDICATIONS AND USAGE Apomorphine hydrochloride injection is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) in patients with advanced Parkinson's disease. Apomorphine hydrocloride inejction has been studied as an adjunct to other medications [see Clinical Studies (14) ] . Apomorphine hydrocloride injection is a non-ergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced Parkinson's disease ( …

2 DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) Always express apomorphine hydrocloride dose in mL to minimize dosing errors ( 2.1 ) The starting dose of apomorphine hydrocloride is 0.2 mL (2 mg); give the first dose under medical supervision; titrate the dose to effect and tolerance; the maximum recommended dose is 0.6 mL ( 2.3 ) Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is recommended, starting 3 days prior to the first dose of apomorphine hydrocloride. …

5 WARNINGS AND PRECAUTIONS For subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of apomorphine hydrocloride ( 5.1 ) Falling asleep during activities of daily living, and daytime somnolence may occur ( 5.3 ) Syncope and hypotension/orthostatic hypotension may occur ( 5.4 ) Falls may occur, or increase ( 5.5 ) May cause hallucinations and psychotic-like behavior ( 5.6 ) May cause dyskinesia or exacerbate pre-existing dyskinesia ( 5.7 ) May cause problems with impulse control …

4 CONTRAINDICATIONS Apomorphine hydrocloride is contraindicated in patients: Using concomitant drugs of the 5HT 3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1) ] . There have been reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron. With hypersensitivity/allergic reaction to apomorphine or to any of the excipients of apomorphine hydrocloride, including a sulfite (i.e., sodium metabisulfite). Angioedema or anaphylaxis may occur [see Warnings and Precautions (5.12) …

Apomorphine Hydrochloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Apomorphine Hydrochloride drug label (National Library of Medicine)
• openFDA — Apomorphine Hydrochloride label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 855856 (NLM Normalized Drug Names)
• NDC Directory — Apomorphine Hydrochloride (FDA National Drug Code)

Medical Disclaimer

The information on this page is intended for educational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication.

Data sources: DailyMed (NLM), openFDA, MFDS