(-)-Apomorphine

267.326

267.32

200-360-0

N21FAR7B4S

DTXSID8022614

Hexagonal plates from chloroform+petroleum ether; rods from ether

G04BE|G - Genito urinary system and sex hormones|N - Nervous system

43.7

3.1

Solid

1.299 g/cm3

195 °C (decomp)

473.4ºC at 760 mmHg

268.8ºC

20g/L(25 ºC)

1.27X10-9 mm Hg at 25 deg C (est)

Peritoneal-mouse LD50: 160 mg/kg; oral-mouse LD50: 300 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

Henry's Law constant = 5.80X10-16 atm-cu m/mol at 25 °C (est)

pKb: 7.0; pKa: 8.92

Decomposes at 195 °C; sublimes in high vacuum; oxidizes rapidly in air & becomes green; solutions darken rapidly|Hydroxyl radical reaction rate constant = 1.61X10-10 cu cm/molec-sec at 25 °C (est)

Treasury is ventilated, low temperature and dry; stored separately from food materials

Contact with the skin can produce dermatitis; weak allergy items

The drug is unstable in solution and must be prepared just prior to use

P261, P264, P270, P271, P272, P280, P285, P301+P310, P301+P312, P302+P352, P304+P312, P304+P340, P304+P341, P312, P321, P322, P330, P333+P313, P342+P311, P363, P405, P501

H301

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl apomorphine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Apomorphine hydrochloride/

|Danger|H301 (95%): Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|Aggregated GHS information provided by 40 companies from 3 notifications to the ECHA C&L Inventory.

highly toxic

Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD50 in mice is 145µg/kg.

Apomorphine has not been reported to cause serum aminotransferase elevations or clinically apparent acute liver injury, but its use has been limited and is typically given in low doses for a limited period of time. Thus, if apomorphine causes liver injury it must be rare.

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 5HT3 antagonist class (including, for example, ondansetron, granisetron , dolasetron, palonosetron, and alosetron) is contraindicated.|Potential pharmacologic interaction (additive sedative and hypotensive effects) with alcohol. Potential pharmacologic interaction with CNS depressants (additive sedative effects).|Hypotensive Agents and Vasodilators: Potential pharmacologic interaction (additive hypotensive effects); use with caution. Hypotension, myocardial infarction, pneumonia, serious falls, and bone and joint injuries reported more frequently in patients receiving concomitant antihypertensive drugs or vasodilators. The mechanism underlying many of these events is unknown, but may be associated with hypotension.|Potential pharmacologic interaction (reduced efficacy of apomorphine) when apomorphine is used with certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide. Patients with major psychosis receiving certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) should receive dopamine agonists only if benefit outweighs risk.|For more Interactions (Complete) data for APOMORPHINE (6 total), please visit the HSDB record page.

LD50 Mouse oral 300 mg/kg|LD50 Mouse ip 160 mg/kg|LD50 Mouse iv 56 mg/kg

The commercially available formulation of apomorphine hydrochloride injection contains sodium metabisulfite, which can cause serious allergic-type reactions in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis. Sulfite sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected.

Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease.|FDA Label|Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.In order for Uprima to be effective, sexual stimulation is required.|Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.In order for Taluvian to be effective, sexual stimulation is required.|Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.In order for Ixense to be effective, sexual stimulation is required.

Apomorphine is a subcutaneously administered dopamine receptor agonist used predominantly in the therapy of hypomobility of advanced Parkinson disease. The use of apomorphine has been limited, but it has not been associated with serum enzyme elevations during treatment nor has it been implicated in cases of acute liver injury.

Antiparkinson Agents

Dopamine Agonists; Emetics|Apomorphine hydrochloride is used for the acute, intermittent management of episodes of hypomobility (i.e., "off" episodes, including both end-of-dose "wearing off" and unpredictable "on-off" episodes) associated with advanced Parkinson's disease. Apomorphine is designated an orphan drug by the US Food and Drug Administration (FDA) for this use.|Apomorphine previously was used for induction of emesis in the acute management of oral poisoning, but it has been abandoned because of its potential for respiratory depression. /Former use/|MEDICATION (VET): ... The safety and efficacy of an ocular insert designed to provide controlled release of apomorphine for the induction of emesis in dogs /was evaluated/. 5,001 dogs treated with ocular apomorphine inserts and 32 dogs treated with IV administration of apomorphine. Data collected on a case report form included breed, body weight, time to emesis after placement of the insert, and any information available regarding the nature of the toxicosis and clinical signs. A list of potential adverse effects was provided, and attending clinicians graded their occurrence by use of a subjective scale. Similar report forms were used for dogs that received apomorphine IV. Treatment was considered successful if emesis occurred within 15 minutes of administration. Safety was assessed by evaluation of the frequency and severity of adverse effects. For the ocular insert and IV injection groups, the success rates were 83.5% and 90.6% respectively, and were not significantly different. Adverse effects were more frequent in the IV group, whereas ocular irritation was most frequent in the insert group. Overall, the ocular inserts provided an alternative to parenteral administration of apomorphine with comparable efficacy and a lower prevalence of adverse effects.|For more Therapeutic Uses (Complete) data for APOMORPHINE (6 total), please visit the HSDB record page.

Retinal degeneration has been observed in albino rats given dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies) and in rats exposed to high-intensity light given these agents for shorter periods; however, retinal degeneration was not observed in a 2-year carcinogenicity study in albino mice or in rats or monkeys given these agents for 1 year. Apomorphine has not been evaluated in carcinogenicity studies; however, apomorphine is expected to cause similar ocular effects in animals. Although the clinical importance of these findings has not been established, the presumed mechanism of action of the effect may be applicable to all vertebrates (e.g., disk shedding).|Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy were reported in a few patients treated with ergot-derivative dopamine receptor agonists. Although these adverse effects presumably are related to the ergoline structure of these compounds, the possibility exists that nonergot-derived drugs that increase dopaminergic activity such as apomorphine may induce similar changes.|Apomorphine may cause or exacerbate dyskinesias. Dyskinesia or worsening of dyskinesia was reported in 24% of patients and resulted in discontinuance of the drug in 2% of patients in clinical studies.|The commercially available formulation of apomorphine hydrochloride injection contains sodium metabisulfite, which can cause serious allergic-type reactions in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis. Sulfite sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.|For more Drug Warnings (Complete) data for APOMORPHINE (28 total), please visit the HSDB record page.

Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval.p

Drugs that bind to and activate dopamine receptors. (See all compounds classified as Dopamine Agonists.)|Agents that cause vomiting. They may act directly on the gastrointestinal tract, bringing about emesis through local irritant effects, or indirectly, through their effects on the chemoreceptor trigger zone in the postremal area near the medulla. (See all compounds classified as Emetics.)

Apomorphine has a plasma T_max of 10-20 minutes and a cerebrospinal fluid T_max. The C_max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported.|Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine.|The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L.|The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h.|The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 - 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.|Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 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 to 8 mg following a single subcutaneous injection of apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease. /Apomorphine hydrochloride/|In the treatment of patients with Parkinson's disease, apomorphine has an established place as a back-up therapy if other antiparkinsonian drugs, such as levodopa and oral dopamine agonists, have not controlled the existing response fluctuations. Apomorphine is a synthetic derivative of morphine, with a totally distinct pharmacological profile. It is a very lipophilic compound which is easily (auto)oxidized. This (auto)oxidation is the main metabolic route besides glucuronidation and sulfation, which are both responsible for about 10% of the metabolic transformation. Apomorphine quickly passes the nasal and intestinal mucosa as well as the blood-brain barrier (depending on the administration route). Many routes of administration have been explored, but subcutaneous, sublingual, nasal and rectal administration are used in clinical practice. The volume of distribution varies between 1 and 2 times bodyweight. The elimination half-life is very short (30 to 90 min) depending on the type of parenteral administration. Apomorphine is a high clearance drug (3 to 5 L/kg/hr) and is mainly excreted and metabolised by the liver. Only 3 to 4% is excreted unchanged in the urine. The clinical effect of apomorphine can be linked directly to its concentration in the cerebrospinal fluid. Consequently, a 2-compartment model can be used to predict the clinical effects of apomorphine. The pharmacokinetic-pharmacodynamic data reflect the clinical observations of steep dose-effect curves if apomorphine is used in patients with random 'on-off' fluctuations. These dose-effect curves are less steep in stable or 'wearing-off' (end-of-dose deterioration) patients. Intravenous infusions of apomorphine in combination with timed motor assessments can be used clinically to characterize the therapeutic window of a particular patient if dyskinesia persists after single injections of apomorphine. If more population data become available, the population pharmacokinetics-pharmacodynamics of apomorphine could be helpful in predicting the clinical effects of apomorphine in the several subgroups of patients with Parkinson's disease.

Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug.|Routes of apomorphine metabolism in humans are not known. Potential metabolic routes include sulfation, N-demethylation, glucuronidation, and oxidation.1 Apomorphine undergoes rapid auto-oxidation in vitro. Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine. In vitro studies have suggested that apomorphine may be metabolized by COMT. Data from in vivo studies indicate that apomorphine is not metabolized by COMT.

The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes.|The mean terminal elimination half-life is about 40 minutes (range about 30 to 60 minutes).

Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown.|The exact mechanism of action of apomorphine hydrochloride in the treatment of Parkinson's disease has not been fully elucidated but may involve stimulation of postsynaptic dopamine D2 receptors within the caudate-putamen in the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits associated with neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ([MPTP])-induced lesions in the ascending nigrostriatal dopaminergic pathway in primates.|Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist that is structurally and pharmacologically related to dopamine. In in vitro studies, apomorphine hydrochloride demonstrated a higher affinity for the dopamine D4 receptor than for dopamine D2, D3, or D5 receptors. Apomorphine hydrochloride binds with moderate affinity to alpha-adrenergic (alpha1D, alpha2B, alpha2C) receptors but has little or no affinity for dopamine D1 receptors, serotonergic (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C) receptors, beta1- or beta2-adrenergic receptors, or histamine H1 receptors. /Apomorphine hydrochloride/

(6aR)-10-methoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-11-ol (apocodeine); morphine

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/|Specific drugs and antidotes: Naloxone is a specific opioid antagonist with no agonist properties of its own; large doses may be given safely. ... Caution: The duration of the effect of naloxone (1-2 hours) is shorter than that of many opioids. Therefore, do not release a patient who has awakened after naloxone treatment until at least 3-4 hours has passed since the last dose of naloxone. In general, if naloxone was required to reverse opioid-induced coma, it is safer to admit the patient for at least 6-12 hours of observation. Nalmefene is an opioid antagonist with a longer duration of effect (3-5 hours). ... /Opiates and opioids/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Opiates and opioids/|Enhanced elimination. Because of the very large volumes of distribution of the opioids and the availability of an effective antidotal treatment, there is no role for enhanced elimination procedures. /Opiates and opioids/|For more Antidote and Emergency Treatment (Complete) data for APOMORPHINE (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ This study was undertaken to ascertain the histopathology and etiology of cutaneous nodules observed in Parkinson's patients treated with continuous subcutaneous apomorphine. Ten patients were recruited, answered questionnaires, and underwent skin biopsies and full blood count, and nine were patch tested to apomorphine and its preservative. Six had serum IgE levels measured. A florid panniculitis was seen in all biopsies; five were predominantly eosinophilic, three lymphocytic and two neutrophilic; in seven cases the panniculitis was mixed and in three it was septal. Patch testing was universally negative and the IgE levels were normal.|/SIGNS AND SYMPTOMS/ A rarely reported motivation for apomorphine abuse (escalation of dose beyond prescribed frequency) is the use of apomorphine to attempt to avoid all symptoms of all "off" events when "off" events occur frequently. A second, rarely reported, motivation for apomorphine abuse is a psychosexual reaction related to the stimulation of penile erection and increase in libido. Adverse events that have been reported in males with overuse include frequent penile erections, atypical sexual behavior, heightened libido, dyskinesias, agitation, confusion, and depression. No studies have been conducted to evaluate the potential for dependence when apomorphine is used as acute (rescue) treatment of "off" episodes in the patients with "on/off" or "wearing-off" effects associated with late stage Parkinson's disease.|/SIGNS AND SYMPTOMS/ 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 relative to younger adults.|/CASE REPORTS/ A similar pattern of psychosexual disorders has been observed after long-term treatment with levodopa therapy in four male parkinsonian patients treated with apomorphine for severe on-off motor fluctuations. An acute episode in each case had led them to the hospital in the context of a psychiatric emergency (after punishable sexual acts in two cases). In each case, this episode had been preceded by an increase of self-administered apomorphine, whereas other antiparkinsonian drugs remained unchanged. Questioning had revealed psychosexual disturbances as early as the onset of apomorphine treatment, which tended to progressively worsen with the number of apomorphine daily doses. A decrease in the dosage of apomorphine had been followed by the improvement of the psychiatric condition without worsening of the motor status. Recurrence of psychiatric disorders with similar features had been observed when two patients again increased the number of apomorphine daily injections. The absence of somatic manifestations when apomorphine treatment was withdrawn or reduced, with persistence of psychosexual disturbances, could suggest a psychological dependence from the drug.|For more Human Toxicity Excerpts (Complete) data for APOMORPHINE (7 total), please visit the HSDB record page.

Apokinon

Parenteral: Injection, for subcutaneous use only: 10 mg/mL Apokyn (with sodium metabisulfite; benzyl alcohol 0.5% in cartridges) (Mylan). /Apomorphine hydrochloride (hemihydrate)/

THIN-LAYER CHROMATOGRAPHY ON SILICA GEL G.|AOAC Method 930.40. Microchemical tests. Alkaloids and related amines in drugs.|AOAC Method 961.18B. Apomorphine in drug tablets.|Analyte: apomorphine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /apomorphine hydrochloride/|For more Analytic Laboratory Methods (Complete) data for APOMORPHINE (14 total), please visit the HSDB record page.

GAS CHROMATOGRAPHIC DETERMINATION OF APOMORPHINE IN URINE & FECES.|Analyte: apomorphine; matrix: blood (whole), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 206.4 nm

Human drugs -> Uprima -> EMA Drug Category|Urologicals -> Human pharmacotherapeutic group|Human drugs -> Taluvian -> EMA Drug Category|Human drugs -> Ixense -> EMA Drug Category|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals