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DOPAMINE RECEPTOR AGONISTS (NON-ERGOT)

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Apomorphine is a non-ergoline dopamine agonist approved for the treatment of advanced Parkinson disease. Apomorphine has high affinity for dopamine-4 (D4) receptors; moderate affinity for the dopamine-2, dopamine-3 and dopamine-5 receptors; and low affinity for dopamine-1, serotonin-1A, 2A, 2B and 2C receptors. Apomorphine exhibits no affinity for histamine H1 or adrenergic beta-1 or beta-2 receptors.
    B) ROPINIRole is a dopamine-2 (D2) receptor agonist approved for the treatment of Parkinson disease. ROPINIRole appears to have selectivity for D2 receptors, but with a higher affinity for dopamine-3(D3) receptors. It is a nonergoline, nonphenolic idolone derivative. Most toxicity is due to its peripheral dopaminergic activity.
    C) Rotigotine is a non-selective (D3/D2/D1), non-ergot dopamine agonist. For information on pramipexole, please refer to PRAMIPEXOLE AND RELATED AGENTS management.

Specific Substances

    A) APOMORPHINE
    1) (-)-Apomorphine
    2) Apomorfin
    3) 1-Apomorphine
    4) CAS 58-00-4
    ROPINIROLE
    1) 4-(2-(Dipropylamino)ethyl)indolin-2-one
    2) rOPINIRole hydrochloride
    3) SKF-101468
    4) SK&F 101468-A
    5) CAS 91374-21-9 (ropinirole)
    6) CAS 91374-20-8 (ropinirole hydrochloride)
    7) Molecular Formula: C16-H24-N2-O
    ROTIGOTINE
    1) Rotigotine hydrochloride
    2) N-0923
    3) SPM-962
    4) CAS 99755-59-6 (rotigotine)
    5) CAS 125572-93-2 (rotigotine hydrochloride)
    6) Molecular Formula: C19-H23-N-O-S

Available Forms Sources

    A) FORMS
    1) APOMORPHINE
    a) Subcutaneous solution: 10 mg/mL (Prod Info APOKYN(R) subcutaneous injection, 2015)
    2) ROPINIROLE
    a) IMMEDIATE-RELEASE ORAL TABLET: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg pentagonal film-coated tablets (Prod Info REQUIP(R) oral tablets, 2014).
    b) EXTENDED-RELEASE ORAL TABLET: 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg biconvex capsule-shaped tablets (Prod Info REQUIP XL(R) oral extended-release tablets, 2014).
    3) ROTIGOTINE
    a) TRANSDERMAL PATCH, EXTENDED-RELEASE: 1 mg/24 hr, 2 mg/24 hr, 3 mg/24 hr, 4 mg/24/hr, 6 mg/24 hr, 8 mg/24 hr (Prod Info NEUPRO(R) transdermal system patch, 2015)
    B) USES
    1) Apomorphine is FDA approved for the treatment of hypomobility, also known as "off" episodes, that can occur intermittently, unpredictably, or at the end of dose weaning period in patients with advanced Parkinson disease (Prod Info APOKYN(R) subcutaneous injection, 2015).
    2) ROPINIRole is used primarily for the treatment of early Parkinson disease, either as a monotherapy or combined with levodopa in advanced disease. ROPINIRole is also FDA approved for the treatment of moderate to severe Restless Legs Syndrome (Prod Info REQUIP(R) oral tablets, 2014).
    3) Rotigotine is indicated for the treatment of Parkinson disease and for the treatment of moderate to severe Restless Legs Syndrome (Prod Info NEUPRO(R) transdermal system patch, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: ROPINIRole, rotigotine, and apomorphine are used for the treatment of Parkinson disease. ROPINIRole is also used for the treatment of restless leg syndrome. Apomorphine is administered subcutaneously, rOPINIRole orally, and rotigotine as a transdermal patch. For information on pramipexole, refer to PRAMIPEXOLE and RELATED AGENTS. PHARMACOLOGY: These agents act by stimulating dopamine D2-type receptors within the caudate-putamen in the brain. Apomorphine has high affinity for dopamine-4 (D4) receptors and moderate affinity for the dopamine-2, dopamine-3 and dopamine-5 receptors. ROPINIRole and rotigotine are selective for the dopamine-2 (D2)-receptor agonist with higher specificity for D3 receptors.
    B) TOXICOLOGY: Overdose effects are related to peripheral and central dopaminergic stimulation.
    C) EPIDEMIOLOGY: Overdose is rare; however, apomorphine abuse has been reported in other countries. Patients may overdose on apomorphine to avoid "off" episodes or to experience an increase in psychosexual stimulation. Male patients with Parkinson disease have been reported to increase the frequency of their injections, leading to heightened libido, stimulation of penile erections, hallucinations, dyskinesia, abnormal behavior, agitation, confusion, and depression.
    D) WITH THERAPEUTIC USE
    1) ROPINIROLE: Spontaneous vomiting and mild hypotension, sweating, nausea, dizziness, and impotence have been reported as adverse effects in clinical trials. The majority of adverse effects are related to the peripheral dopaminergic activity of rOPINIRole.
    2) ROTIGOTINE: Nausea, vomiting, somnolence, dizziness, headache, and application site reactions are the most frequently reported adverse effects reported with rotigotine therapy. For information on pramipexole, please refer to PRAMIPEXOLE AND RELATED AGENTS management.
    3) APOMORPHINE: Yawning, dyskinesia, somnolence, dizziness, rhinorrhea, edema, chest pain, increased sweating, flushing, and pallor have been reported in clinical trials. Severe nausea and vomiting has been reported with therapeutic doses.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING:
    a) Headache, nasal congestion, dryness of mouth, nausea, vomiting, flushing, coughing, fatigue.
    b) ROPINIROLE: Of patients receiving inadvertent doses greater than 24 mg/day, one experienced mild orofacial dyskinesia, and another had transient nausea. Other effects reported after unintentional overdose (a dose greater than 24 mg/day) included visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Doses of 24 mg or less or overdoses of unknown amounts have been associated with the following effects: vomiting, increased coughing, fatigue, syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusion.
    c) ROTIGOTINE: There have been no reports of overdose; however, in the event of an overdose, the following primary symptoms may be expected: nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, seizures, and other signs of excessive dopaminergic stimulation.
    2) SEVERE POISONING:
    a) Orthostatic hypotension, bradycardia, hypothermia, supraventricular ectopy, chest pain, lethargy, dizziness, euphoria, dyskinesias, agitation, confusion, mydriasis, drowsiness, sedation, vomiting, nausea, visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, nightmares, syncope, somnolence, involuntary movements, seizures, ataxia, and other signs of excessive dopaminergic stimulation.
    b) APOMORPHINE: Loss of consciousness, bradycardia, and hypotension were reported in a patient who received 25 mg of apomorphine.
    0.2.7) NEUROLOGIC
    A) Lethargy, dizziness, and euphoria have been reported as adverse effects. Increased dyskinesias have been reported.
    0.2.20) REPRODUCTIVE
    A) Apomorphine, rOPINIRole, and rotigotine are all classified as FDA pregnancy category C. Adverse fetal effects were observed in animal studies with rotigotine at maternal doses that were less than or approximately equal to those used clinically. ROPINIRole and rotigotine have been found in the breast milk of rats. It is unknown whether these drugs are excreted in human milk.

Laboratory Monitoring

    A) Monitor vital signs and ECG in symptomatic patients.
    B) Monitor for CNS depression.
    C) Monitor fluid and electrolyte balance in patients with prolonged vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat dyskinesias by decreasing the dose and providing supportive care. Treat dystonia with benzodiazepines and antispasmodic agents (benztropine, diphenhydramine). Treat hypotension with IV fluids and treat dysrhythmias with routine antiarrhythmic agents.
    C) DECONTAMINATION
    1) Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected. Due to the mechanism of action of dopamine D2 receptor agonists, spontaneous vomiting is expected to occur following an overdose. Remove rotogotine patch and wash exposed skin.
    D) AIRWAY MANAGEMENT
    1) None.
    E) DYSTONIA
    1) Dystonias may respond to diazepam, diphenhydramine or benztropine. ADULT: Benztropine is dosed at 1 to 4 mg IV or IM, maximum 6 mg/day. Diphenhydramine is dosed at 25 to 50 mg IV over 2 minutes. PEDIATRIC: Diphenhydramine: 1.25 mg/kg/dose IV over 2 minutes.
    F) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine. Central venous pressure monitoring may be indicated to guide fluid therapy in patients with persistent hypotension. Administer atropine if hypotension is secondary to bradycardia. If hypotension persists administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; PEDIATRIC: begin infusion at 0.1 mcg/kg/min); titrate to desired response
    G) CONDUCTION DISORDER OF THE HEART
    1) Monitor for dysrhythmias and treat with routine antiarrhythmic agents.
    H) NAUSEA AND VOMITING
    1) APOMORPHINE ONLY: Use of a 5HT3 antagonist (ondansetron, granisetron, dolasetron, palonosetron and alosetron) is contraindicated. Use of apomorphine with ondansetron has resulted in profound hypotension and loss of consciousness. In clinical trials, trimethobenzamide was use as the primary therapy for apomorphine induced nausea and/or vomiting.
    I) ENHANCED ELIMINATION PROCEDURE
    1) These agents have large volumes of distribution, methods to enhance elimination would not be effective.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic after inadvertent ingestion can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients and those with deliberate ingestions should be sent to a medical facility for evaluation and treatment.
    3) ADMISSION CRITERIA: All patients who remain symptomatic after 6 to 12 hours of observation should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist for assistance with medical management if the patient has more than moderate symptoms or symptoms not consistent with the exposure or the diagnosis is unclear.
    K) PITFALLS
    1) When managing overdose with dopamine receptor antagonists, the possibility of coingestion with other agents should be considered.
    L) PHARMACOKINETICS
    1) ROPINIROLE: Rapidly absorbed. Oral bioavailability is 55%, onset of effect is 1 to 2 hours. It is 40% protein bound with a volume of distribution of 7.5 L/kg. It undergoes hepatic metabolism with an elimination half life of 6 hours. ROTIGOTINE: After transdermal application, about 45% is absorbed in 24 hours. Bioavailability varies by site of application, ranging from less than 1% to 64%. It is 92% protein bound with a volume of distribution of 84 L/kg. It undergoes hepatic metabolism with an elimination half life of 5 to 7 hours. APOMORPHINE: Lipophilic and rapidly absorbed via subcutaneous administration into the abdominal wall. Bioavailability is 100%, time to peak concentration is 10 to 60 minutes and volume of distribution is 218 L. Elimination half life is about 40 minutes
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (vasodilators, beta blockers, calcium channel blockers) or medications that cause dystonia or dyskinesia (antipsychotics, neuroleptics) or other medications that can alter the dopamine-mediated functions of the basal ganglia.

Range Of Toxicity

    A) TOXICITY: There is limited overdose experience with these agents. APOMORPHINE: A man experienced loss of consciousness, but recovered fully after injecting 25 mg. ROPINIROLE: An adult survived an ingestion of 435 mg over a 7-day period (62.1 mg/day). PEDIATRICS: Inadvertent exposures in children generally cause only mild effects.
    B) THERAPEUTIC DOSE: APOMORPHINE: Recommended daily dose, after the dose-determination titration, is 0.2 to 0.6 mL (2 to 6 mg) SubQ as needed for "off" episodes. MAXIMUM DOSE: 0.6 mL (6 mg) per day. ROPINIROLE: IMMEDIATE RELEASE: Parkinson disease: Initial titration: 0.25 mg 3 times daily, then increase dose in 0.25 mg to 3 mg increments weekly to achieve therapeutic response; MAXIMUM DOSE: 24 mg/day. Restless Legs Syndrome: Initial dose: 0.25 mg/day, titrate to a maximum dose of 4 mg once daily. EXTENDED-RELEASE: Parkinson disease: Initially 2 mg once daily for 1 to 2 weeks; may be increased by 2 mg/day increments weekly. MAXIMUM DOSE: 24 mg/day. ROTIGOTINE: Early stage Parkinson disease: Initial dose: 2 mg/day patch once daily. May increase weekly by 2 mg/24 hour increments if needed and as tolerated. MAXIMUM DOSE: 6 mg/day. Advanced stage Parkinson disease: Initial dose: 4 mg/day patch once daily. May increase weekly by 2 mg/24 hour increments if needed and as tolerated. MAXIMUM DOSE: 8 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: ROPINIRole, rotigotine, and apomorphine are used for the treatment of Parkinson disease. ROPINIRole is also used for the treatment of restless leg syndrome. Apomorphine is administered subcutaneously, rOPINIRole orally, and rotigotine as a transdermal patch. For information on pramipexole, refer to PRAMIPEXOLE and RELATED AGENTS. PHARMACOLOGY: These agents act by stimulating dopamine D2-type receptors within the caudate-putamen in the brain. Apomorphine has high affinity for dopamine-4 (D4) receptors and moderate affinity for the dopamine-2, dopamine-3 and dopamine-5 receptors. ROPINIRole and rotigotine are selective for the dopamine-2 (D2)-receptor agonist with higher specificity for D3 receptors.
    B) TOXICOLOGY: Overdose effects are related to peripheral and central dopaminergic stimulation.
    C) EPIDEMIOLOGY: Overdose is rare; however, apomorphine abuse has been reported in other countries. Patients may overdose on apomorphine to avoid "off" episodes or to experience an increase in psychosexual stimulation. Male patients with Parkinson disease have been reported to increase the frequency of their injections, leading to heightened libido, stimulation of penile erections, hallucinations, dyskinesia, abnormal behavior, agitation, confusion, and depression.
    D) WITH THERAPEUTIC USE
    1) ROPINIROLE: Spontaneous vomiting and mild hypotension, sweating, nausea, dizziness, and impotence have been reported as adverse effects in clinical trials. The majority of adverse effects are related to the peripheral dopaminergic activity of rOPINIRole.
    2) ROTIGOTINE: Nausea, vomiting, somnolence, dizziness, headache, and application site reactions are the most frequently reported adverse effects reported with rotigotine therapy. For information on pramipexole, please refer to PRAMIPEXOLE AND RELATED AGENTS management.
    3) APOMORPHINE: Yawning, dyskinesia, somnolence, dizziness, rhinorrhea, edema, chest pain, increased sweating, flushing, and pallor have been reported in clinical trials. Severe nausea and vomiting has been reported with therapeutic doses.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING:
    a) Headache, nasal congestion, dryness of mouth, nausea, vomiting, flushing, coughing, fatigue.
    b) ROPINIROLE: Of patients receiving inadvertent doses greater than 24 mg/day, one experienced mild orofacial dyskinesia, and another had transient nausea. Other effects reported after unintentional overdose (a dose greater than 24 mg/day) included visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Doses of 24 mg or less or overdoses of unknown amounts have been associated with the following effects: vomiting, increased coughing, fatigue, syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusion.
    c) ROTIGOTINE: There have been no reports of overdose; however, in the event of an overdose, the following primary symptoms may be expected: nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, seizures, and other signs of excessive dopaminergic stimulation.
    2) SEVERE POISONING:
    a) Orthostatic hypotension, bradycardia, hypothermia, supraventricular ectopy, chest pain, lethargy, dizziness, euphoria, dyskinesias, agitation, confusion, mydriasis, drowsiness, sedation, vomiting, nausea, visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, nightmares, syncope, somnolence, involuntary movements, seizures, ataxia, and other signs of excessive dopaminergic stimulation.
    b) APOMORPHINE: Loss of consciousness, bradycardia, and hypotension were reported in a patient who received 25 mg of apomorphine.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPOTHERMIA has been reported in patients receiving rOPINIRole and other dopamine agonists. A direct cause-effect relationship has not been clearly established (Pfeiffer, 1990).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS is an expected overdose effect based on its mechanism as a dopamine agonist.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) APOMORPHINE: Hypotension, orthostatic hypotension, and/or syncope occurred at therapeutic doses in 11% (59 of 550) of patients with advanced Parkinson disease in clinical trials (Prod Info APOKYN(R) subcutaneous injection, 2009).
    b) ROPINIROLE: Symptomatic postural hypotension may occur even with low doses of rOPINIRole (Prod Info REQUIP(R) oral tablets, 2006; Rascol, 1996; de Mey et al, 1991; Kleedorfer et al, 1991; Vidailhet et al, 1990; Kapoor et al, 1989) .
    1) ONSET: Hypotensive effects occur within 3 minutes of standing, usually between 2 and 4 hours subsequent to an oral dose (de Mey et al, 1991). Overdoses may be expected to produce a more profound hypotensive effect.
    c) ROTIGOTINE: The incidence of orthostatic hypotension is similar in patients receiving rotigotine therapy as compared with patients receiving a placebo during clinical trials (5% vs 4%); however, analysis of adverse effect terms suggestive of orthostatic hypotension, including dizziness and postural dizziness, showed a 2-fold higher incidence of these effects in patients receiving rotigotine as compared with the placebo group (22% vs 11%) (Prod Info NEUPRO(R) transdermal patch, 2004).
    2) WITH POISONING/EXPOSURE
    a) APOMORPHINE: Hypotension was reported in a patient who received an overdose of apomorphine 25 mg (Prod Info APOKYN(R) subcutaneous injection, 2009).
    b) ROPINIROLE: Orthostatic hypotension and chest pain have been reported following unintentional overdose at doses of 24 mg or less or for overdoses of an unknown amount (Prod Info REQUIP(R) oral tablets, 2006).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE
    1) Hypertension has been reported during therapeutic administration of rOPINIRole (Prod Info REQUIP(R) oral tablets, 2006).
    b) INCIDENCE: 5% of patients treated with rOPINIRole versus 3% in the placebo group developed hypertension (Prod Info REQUIP(R) oral tablets, 2006).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Bradycardia has been reported as an adverse effect following orthostatic hypotension in clinical trials (Vidailhet et al, 1990), and may occur following overdoses.
    2) WITH POISONING/EXPOSURE
    a) Bradycardia was reported in a patient who received an overdose of apomorphine 25 mg (Prod Info APOKYN(R) subcutaneous injection, 2009).
    D) ECTOPIC BEATS
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Supraventricular ectopy has been reported rarely after low doses of rOPINIRole and may potentially occur following overdoses. This has also been reported after pergolide and levodopa (Acton & Broom, 1989).
    E) PALPITATIONS
    1) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Palpitations have been reported in patients who received rOPINIRole doses greater than 24 mg/day (Prod Info REQUIP(R) oral tablets, 2006).

Neurologic

    3.7.1) SUMMARY
    A) Lethargy, dizziness, and euphoria have been reported as adverse effects. Increased dyskinesias have been reported.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE
    1) Drowsiness, somnolence, ataxia, dizziness, and euphoria have been reported in some patients following therapeutic doses of rOPINIRole (Kreider et al, 1996; Rascol, 1996)Wheadon et al, 1996(Kleedorfer et al, 1991; Vidailhet et al, 1990) .
    2) INCIDENCE: Dizziness and somnolence were reported in 39% and 26% of patients, respectively, in one clinical study (Rascol et al, 1996a).
    3) In a 7-year review of Poison Control Centers data, drowsiness developed in 9 of 29 patients (age, 18 months to 4 years) following the unintentional ingestion of pramipexole (n=22; ingested doses: 9 cases less than 0.5 mg; 5 cases 0.5 to 1 mg; 6 cases more than 1 mg; 2 cases unknown) or rOPINIRole (n=7; 3 cases less than 1 mg; 2 cases more than 1 mg; 2 cases unknown) (DesLauriers et al, 2008).
    b) ROTIGOTINE
    1) Somnolence is a frequent occurrence with rotigotine therapy. During clinical trials, somnolence occurred in 25% of patients receiving rotigotine (n=649) as compared with 16% of patients receiving placebo (n=289) (Prod Info NEUPRO(R) transdermal patch, 2004).
    B) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) An accidental overdose of 25 mg (therapeutic dose 6 mg) injected subcutaneously occurred in a 62-year-old man. Approximately 3 minutes after injection, the patient became nauseated and lost consciousness for 20 minutes. Afterwards, the patient was alert with a heart rate of 40 beats/minute and a supine blood pressure of 90/50. He completely recovered within an hour (Prod Info APOKYN(R) subcutaneous injection, 2009).
    2) ROPINIROLE
    a) INCIDENCE: Syncope has been observed as an adverse effect in clinical trials in up to 12% of patients (Prod Info REQUIP(R) oral tablets, 2006).
    C) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Increased dyskinesias have been reported in clinical trials following therapeutic doses (Kreider et al, 1996; Rascol et al, 1996a) .
    1) INCIDENCE: 34% of patients during clinical trials developed dyskinesia (Prod Info REQUIP(R) oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Increased symptoms of dyskinesia have been reported following unintentional overdose of rOPINIRole at doses of 24 mg or less or with overdoses of unknown amounts (Prod Info REQUIP(R) oral tablets, 2006).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Dizziness has been frequently reported with therapy (Prod Info REQUIP(R) oral tablets, 2006).
    1) INCIDENCE: Up to 40% of patients developed dizziness during clinical trials as compared with 22% of patients receiving placebo (Prod Info REQUIP(R) oral tablets, 2006).
    b) ROTIGOTINE: Dizziness was reported in 18% of patients who received rotigotine therapy (n=649) as compared with 11% of patients who received a placebo (n=289) during clinical trials (Prod Info NEUPRO(R) transdermal patch, 2004).
    c) APOMORPHINE: Dizziness was reported in 35% of patients taking apomorphine (n=20) compared with placebo (n=9) in clinical trials (Prod Info APOKYN(R) subcutaneous injection, 2009).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ROTIGOTINE: Headaches were reported in 14% of patients who received rotigotine (n=649) during clinical trials as compared with 10% of patients who received a placebo (n=289) (Prod Info NEUPRO(R) transdermal patch, 2004).
    F) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Of patients receiving 24 mg/day or less, or for overdoses of an unknown amount, the following CNS effects were reported: agitation, somnolence, and confusion (Prod Info REQUIP(R) oral tablets, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) APOMORPHINE: Severe nausea and vomiting have been reported with therapeutic use. Patients are advised to use concomitant antiemesis therapy while on apomorphine. Use of a 5HT3 antagonist (ie, ondansetron, granisetron, palonosetron) is contraindicated. In clinical trials, trimethobenzamide was used with study patients (Prod Info APOKYN(R) subcutaneous injection, 2009).
    b) ROPINIROLE: Nausea and vomiting are common adverse events and are related to peripheral dopaminergic activity. Nausea and vomiting can occur in both the supine and standing positions (Rascol, 1996; de Mey et al, 1991; Acton & Broom, 1989; Kapoor et al, 1989).
    c) In a 7-year review of Poison Control Centers data, vomiting developed in 10 of 29 patients (age, 18 months to 4 years) following the unintentional ingestion of pramipexole (n=22; ingested doses: 9 cases less than 0.5 mg; 5 cases 0.5 to 1 mg; 6 cases more than 1 mg; 2 cases unknown) or rOPINIRole (n=7; 3 cases less than 1 mg; 2 cases more than 1 mg; 2 cases unknown) (DesLauriers et al, 2008).
    d) ROTIGOTINE: Nausea and vomiting are frequent with rotigotine therapy. During clinical trials, nausea and vomiting were reported in 38% and 13% of patients, respectively, who received rotigotine therapy (n=649) as compared with 15% and 2% of patients, respectively, who received a placebo (n=289) (Prod Info NEUPRO(R) transdermal patch, 2004).
    2) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Nausea and vomiting have been reported in patients following unintentional overdoses of greater than 24 mg/day (Prod Info REQUIP(R) oral tablets, 2006).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Dry mouth and constipation may occur as a result of the dopamine agonist properties of rOPINIRole (Prod Info REQUIP(R) oral tablets, 2006).
    C) WEIGHT GAIN FINDING
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE: Weight gain of more than 10% of baseline weight was reported in 3% of patients who received rotigotine (n=649) during clinical trials as compared with less than 1% of patients who received a placebo (n=289). The weight gain appeared to be often associated with the development of peripheral edema (Prod Info NEUPRO(R) transdermal patch, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) ROPINIROLE : Flushing was reported in 13% of patients in a rOPINIRole clinical study, as opposed to 0% in placebo-treated patients (Rascol et al, 1996).
    b) APOMORPHINE: Flushing was reported as a common adverse event in clinical trials (Prod Info APOKYN(R) subcutaneous injection, 2009).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) APOMORPHINE: Hyperhidrosis was reported as a common adverse event with therapeutic use of apomorphine in clinical trials (Prod Info APOKYN(R) subcutaneous injection, 2009).
    2) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Hyperhidrosis has been reported in patients following overdoses of greater than 24 mg/day (Prod Info REQUIP(R) oral tablets, 2006).
    C) APPLICATION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) ROTIGOTINE: Application site reactions, including localized erythema, edema, and pruritus, have been frequently reported with rotigotine therapy. In 3 double-blind placebo-controlled trials, application site reactions were reported in 37% of patients who received rotigotine (n=629) as compared with 14% in the placebo group (n=289) (Prod Info NEUPRO(R) transdermal patch, 2004).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ISOLATED PROLACTIN DEFICIENCY
    1) WITH POISONING/EXPOSURE
    a) ROPINIROLE: Decreased serum prolactin levels may occur following overdoses. Decreases have occurred in patients in clinical trials, and this effect is presumably related to peripheral dopaminergic activity, and is evident within 45 minutes of oral administration (de Mey et al, 1991; de Mey et al, 1990a; Acton & Broom, 1989) .

Reproductive

    3.20.1) SUMMARY
    A) Apomorphine, rOPINIRole, and rotigotine are all classified as FDA pregnancy category C. Adverse fetal effects were observed in animal studies with rotigotine at maternal doses that were less than or approximately equal to those used clinically. ROPINIRole and rotigotine have been found in the breast milk of rats. It is unknown whether these drugs are excreted in human milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) ROTIGOTINE
    a) RATS: SubQ doses of rotigotine 0.5, 1.5, and 5 mg/kg/day administered to pregnant rats during organogenesis resulted in increased fetal death at all doses. The 0.5 mg/kg/day dose is less than the maximum recommended human dose (MRHD) on a mg/m(2) basis. Doses of 1 mg/kg/day given during gestation day 6 to postnatal day 21 led to impaired growth and development during lactation and caused neurobehavioral abnormalities in offspring (Prod Info NEUPRO transdermal patch, 2012).
    b) MICE: No effects occurred at rotigotine subQ doses of 10 mg/kg/day (approximately 6 times the MRHD for Parkinson disease on a mg/m(2) basis) during organogenesis; however, increased incidence of fetal skeletal retardation and death occurred at doses of 30 mg/kg/day and 90 mg/kg/day, respectively (Prod Info NEUPRO transdermal patch, 2012).
    c) RABBITS: No effects occurred at rotigotine subQ doses of 5 mg/kg/day (approximately 12 times the MRHD on a mg/m(2) basis) during organogenesis; however, increased fetal deaths occurred at doses of 10 and 30 mg/kg/day, respectively (Prod Info NEUPRO transdermal patch, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The following agents have been classified as FDA pregnancy category C: apomorphine, rOPINIRole, and rotigotine (Prod Info NEUPRO transdermal patch, 2012; Prod Info APOKYN(R) subcutaneous injection, 2009; Prod Info REQUIP(R) oral tablets, 2006)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) APOMORPHINE
    a) It is not known if apomorphine is excreted in human milk (Prod Info APOKYN(R) subcutaneous injection, 2009).
    B) BREAST FEEDING
    1) ROPINIROLE: Inhibits prolactin secretion in humans. It has been found in the breast milk of rats; however, it is unknown whether it is excreted in human milk (Prod Info REQUIP(R) oral tablets, 2006).
    2) ROTIGOTINE: Studies have shown that rotigotine is excreted in the breast milk of rats; it is unknown whether it is excreted in human milk. Rotigotine reduces prolactin secretion in humans, therefore inhibition of lactation is expected. (Prod Info NEUPRO transdermal patch, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) ROTIGOTINE
    a) RATS: An absence of implantation was reported following rotigotine subQ administration to female rats prior to/during mating and through gestation day 7 at doses of 1.5 mg/kg/day (2 times the maximum recommended human dose (MRHD) on a mg/m(2) basis). No effect on fertility was observed in male rats treated with 1.5, 5, or 15 mg/kg/day from 70 days prior to and during mating; however, a decrease in epididymal sperm motility was noted at the 15 mg/kg/day dose. The 5 mg/kg/day dose is 6 times the MRHD on a mg/m(2) basis (Prod Info NEUPRO transdermal patch, 2012).
    b) MICE: A markedly decreased or complete absence of implantation was reported following rotigotine subQ administration to female mice from 2 weeks until 4 days before mating at doses of 10, 30, and 90 mg/kg/day and then from 3 days before mating until gestation day 7 at a dose of 6 mg/kg/day (approximately 4 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) (Prod Info NEUPRO transdermal patch, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and ECG in symptomatic patients.
    B) Monitor for CNS depression.
    C) Monitor fluid and electrolyte balance in patients with prolonged vomiting.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor fluid and electrolyte balance in patients with prolonged vomiting.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor ECG in symptomatic patients for possible bradyarrhythmias.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) ROPINIROLE -
    a) Plasma levels of rOPINIRole have been quantitatively measured using a high- performance liquid chromatographic determination with ultra violet detection (Swagzdis & Mico, 1986).
    b) de Mey et al (1991) measured rOPINIRole in human plasma using a radio- immunoassay developed by Smith Kline and French.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients who remain symptomatic after 6 to 12 hours of observation should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic after inadvertent ingestion can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist for assistance with medical management if the patient has more than moderate symptoms or symptoms not consistent with the exposure or the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients and those with deliberate ingestions should be sent to a medical facility for evaluation and treatment.

Monitoring

    A) Monitor vital signs and ECG in symptomatic patients.
    B) Monitor for CNS depression.
    C) Monitor fluid and electrolyte balance in patients with prolonged vomiting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and ECG in symptomatic patients. Monitor for CNS depression. Monitor fluid and electrolyte balance in patients with prolonged vomiting.
    B) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) Administer atropine if hypotension is secondary to bradycardia.
    D) NAUSEA AND VOMITING
    1) APOMORPHINE ONLY: Use of a 5HT3 antagonist (ondansetron, granisetron, dolasetron, palonosetron and alosetron) is contraindicated. Use of apomorphine with ondansetron has resulted in profound hypotension and loss of consciousness. In clinical trials, trimethobenzamide was used as the primary therapy for apomorphine induced nausea and/or vomiting (Prod Info APOKYN(R) subcutaneous injection, 2009).
    E) CONDUCTION DISORDER OF THE HEART
    1) Monitor for dysrhythmias and treat with routine antiarrhythmic agents.

Enhanced Elimination

    A) HEMODIALYSIS
    1) These agents have large volumes of distribution, methods to enhance elimination would not be effective.

Range Of Toxicity

Summary

    A) TOXICITY: There is limited overdose experience with these agents. APOMORPHINE: A man experienced loss of consciousness, but recovered fully after injecting 25 mg. ROPINIROLE: An adult survived an ingestion of 435 mg over a 7-day period (62.1 mg/day). PEDIATRICS: Inadvertent exposures in children generally cause only mild effects.
    B) THERAPEUTIC DOSE: APOMORPHINE: Recommended daily dose, after the dose-determination titration, is 0.2 to 0.6 mL (2 to 6 mg) SubQ as needed for "off" episodes. MAXIMUM DOSE: 0.6 mL (6 mg) per day. ROPINIROLE: IMMEDIATE RELEASE: Parkinson disease: Initial titration: 0.25 mg 3 times daily, then increase dose in 0.25 mg to 3 mg increments weekly to achieve therapeutic response; MAXIMUM DOSE: 24 mg/day. Restless Legs Syndrome: Initial dose: 0.25 mg/day, titrate to a maximum dose of 4 mg once daily. EXTENDED-RELEASE: Parkinson disease: Initially 2 mg once daily for 1 to 2 weeks; may be increased by 2 mg/day increments weekly. MAXIMUM DOSE: 24 mg/day. ROTIGOTINE: Early stage Parkinson disease: Initial dose: 2 mg/day patch once daily. May increase weekly by 2 mg/24 hour increments if needed and as tolerated. MAXIMUM DOSE: 6 mg/day. Advanced stage Parkinson disease: Initial dose: 4 mg/day patch once daily. May increase weekly by 2 mg/24 hour increments if needed and as tolerated. MAXIMUM DOSE: 8 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) APOMORPHINE
    a) PARKINSON DISEASE
    1) The recommended daily dose after dose determination has been completed is 0.2 to 0.6 mL (2 to 6 mg) SubQ as needed for "off" episodes. MAXIMUM DOSE: 0.6 mL (6 mg) per day (Prod Info APOKYN(R) subcutaneous injection, 2015).
    2) Due to the high incidence of severe nausea and vomiting caused at therapeutic doses with apomorphine, any patient naive to therapy must be titrated on the basis of effectiveness and tolerance. It is recommended that patients on apomorphine be premedicated with oral trimethobenzamide for 3 days prior to initial dose of apomorphine and continued for at least the first 2 months of apomorphine therapy (Prod Info APOKYN(R) subcutaneous injection, 2015).
    2) ROPINIROLE
    a) PARKINSON DISEASE
    1) IMMEDIATE-RELEASE TABLETS: The recommended initial dose is 0.25 mg orally three times daily. After week 4 of therapy, the dose may be increased by 1.5 mg/day increments on a weekly basis up to 9 mg/day, then increased by 3 mg/day increments up to a total dose of 24 mg/day (Prod Info REQUIP(R) oral tablets, 2014).
    2) EXTENDED-RELEASE TABLETS: The recommended initial dose is 2 mg orally once daily for 1 to 2 weeks. The dose may be increased by 2 mg/day increments on a weekly basis or longer, up to a maximum recommended dose of 24 mg/day (Prod Info REQUIP XL(R) oral extended-release tablets, 2014).
    b) RESTLESS LEGS SYNDROME
    1) IMMEDIATE-RELEASE TABLETS: The recommended initial dose 0.25 mg orally once daily, given 1 to 3 hours before bedtime. After 2 days of therapy, the dose may be increased to 0.5 mg once daily, and then to 1 mg once daily by the end of the first week of dosing. After the first week of dosing, the dose may then be increased by 0.5 mg increments on a weekly basis, up to a maximum dose of 4 mg once daily (Prod Info REQUIP(R) oral tablets, 2014).
    3) ROTIGOTINE
    a) EARLY-STAGE PARKINSON DISEASE
    1) Initially, a rotigotine transdermal patch, consisting of 2 mg/24 hours, is applied once daily. The dose may be increased weekly by 2 mg/24 hour increments if needed and as tolerated, up to 6 mg/24 hours (MAXIMUM DOSE) (Prod Info NEUPRO(R) transdermal system patch, 2015).
    2) WITHDRAWAL OF THERAPY: If rotigotine therapy is discontinued, it is necessary to discontinue therapy gradually in order to prevent withdrawal-emergent-hyperpyrexia and confusion. Reduce the daily dose by a maximum of 2 mg/24 hours, preferably every other day, until complete withdrawal of rotigotine (Prod Info NEUPRO(R) transdermal system patch, 2015).
    b) ADVANCED-STAGE PARKINSON DISEASE
    a) Initially, 4 mg TRANSDERMALLY every 24 hours; may increase weekly by 2 mg/24 hours to the recommended dose of 8 mg/24 hours (Prod Info NEUPRO(R) transdermal system patch, 2015)
    b) WITHDRAWAL OF THERAPY: In order to prevent withdrawal-emergent-hyperpyrexia and confusion, discontinue by reducing the dose by a maximum of 2 mg/24 hour increments, preferably every other day, until complete withdrawal of rotigotine (Prod Info NEUPRO(R) transdermal system patch, 2015)
    c) RESTLESS LEGS SYNDROME
    1) Initially, 1 mg TRANSDERMALLY every 24 hours; may increase weekly by 1 mg/24 hours to 3 mg/24 hours (MAXIMUM DOSE) (Prod Info NEUPRO(R) transdermal system patch, 2015)
    2) WITHDRAWAL OF THERAPY: In order to prevent withdrawal-emergent-hyperpyrexia and confusion, discontinue by reducing the dose in 1 mg/24 hour increments, preferably every other day, until complete withdrawal of rotigotine (Prod Info NEUPRO(R) transdermal system patch, 2015)
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) Safety and efficacy of these drugs in pediatric patients have not been established (Prod Info APOKYN(R) subcutaneous injection, 2015; Prod Info NEUPRO(R) transdermal system patch, 2015; Prod Info REQUIP(R) oral tablets, 2014; Prod Info REQUIP XL(R) oral extended-release tablets, 2014).

Minimum Lethal Exposure

    A) ADULT
    1) The minimum lethal SubQ dose of apomorphine is 5 mcg/kg in humans (RTECS, 2006).
    2) The minimum lethal intravenous dose of apomorphine is 0.01 mg/kg (RTECS, 2006).

Maximum Tolerated Exposure

    A) APOMORPHINE
    1) An inadvertent SubQ exposure of 25 mg (therapeutic max dose 6 mg) occurred in a 62-year-old man. Approximately 3 minutes after injection, the patient became nauseated and lost consciousness for 20 minutes. Afterwards, the patient was alert with a heart rate of 40 beats/minute and a supine blood pressure of 90/50. He completely recovered within an hour (Prod Info APOKYN(R) subcutaneous injection, 2015).
    B) ROPINIROLE
    1) The largest overdose reported in premarketing trials was 435 mg taken over a 7-day period (62.1 mg/day); the individual survived (Prod Info REQUIP(R) oral tablets, 2014; Prod Info REQUIP(R) oral tablets, 2006).
    2) Of the limited number of patients that received doses greater than 24 mg/day, one developed orofacial dyskinesia and another experienced intermittent nausea. Other symptoms that have been reported included: agitation, confusion, increased dyskinesia, visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, nightmares, drowsiness, sedation, orthostatic hypotension, chest pain, vomiting and nausea (Prod Info REQUIP(R) oral tablets, 2014; Prod Info REQUIP(R) oral tablets, 2006).
    3) In a 7-year review of Poison Control Centers data, 29 patients (age range, 18 months to 4 years) with unintentional ingestions of pramipexole (n=22; ingested doses: 9 cases less than 0.5 mg; 5 cases 0.5 to 1 mg; 6 cases more than 1 mg; 2 cases unknown) or rOPINIRole (n=7; 3 cases less than 1 mg; 2 cases more than 1 mg; 2 cases unknown) were identified. Overall, 9 patients had no effect, 16 had a minor effect (vomiting =10 patients; drowsiness = 9 patients), and 3 had unrelated effects (DesLauriers et al, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) APOMORPHINE
    B) ROPINIROLE

Pharmacology Toxicology

Pharmacologic Mechanism

    A) APOMORPHINE
    1) Apomorphine is a non-ergoline dopamine agonist approved for the treatment of Parkinson disease. The exact mechanism of action is unknown, however, it is thought that it's action is due to stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. Apomorphine has high affinity for dopamine-4 (D4) receptors; moderate affinity for the dopamine-2, dopamine-3 and dopamine-5 receptors; and low affinity for dopamine-1, serotonin-1A, 2A, 2B and 2C receptors. Apomorphine exhibits no affinity for histamine H1 or adrenergic beta-1 or beta-2 receptors (Prod Info APOKYN(R) subcutaneous injection, 2015; Prod Info APOKYN(R) subcutaneous injection, 2009).
    B) ROPINIROLE
    1) DOPAMINE D2 AGONIST: ROPINIROLE, a selective dopamine-2 (D2) -receptor agonist with higher specificity for D3 receptors is indicated in the treatment of Parkinson disease (de Mey et al, 1990; Anon, 1996). It is a nonergoline, nonphenolic indolone derivative. In preclinical studies, a high selectivity of rOPINIRole for D2 receptors, without significant activity at other receptor types, was demonstrated (Eden et al, 1991). The drug binds to all 3 D2-receptor subtypes (D2A, D2B, and D2C) (Parker et al, 1994), and exhibits D2 agonist activity both peripherally and centrally, the latter being a determinant of effects of the drug in parkinsonism (Parker et al, 1994; de Mey et al, 1991).
    2) D3 RECEPTOR SELECTIVITY: Bowen et al (1993) have demonstrated estimated Ki (high affinity site: nM) for human and rat D2 and D3 clones to be 950 and 99, respectively, for rOPINIRole dopamine receptor sites, concluding that rOPINIRole also has selectivity for the cloned D3 receptors (Bowen et al, 1993).
    3) DECREASED SERUM PROLACTIN levels were demonstrated in healthy human subjects given single oral doses (0.08 to 2.5 mg) of rOPINIRole. This effect was dose-related in one study (de Mey et al, 1990), but not clearly so in another (Acton & Broom, 1989).
    4) POSTURAL HYPOTENSION AND NAUSEA occurred at higher doses in clinical studies in healthy human volunteers. Domperidone (20 mg) given 1 hour prior to rOPINIRole effectively prevented rOPINIRole-induced postural symptoms, including nausea and malaise (de Mey et al, 1991).
    C) ANIMAL STUDIES
    1) ROPINIROLE: Marmosets with MPTP induced parkinsonism showed a reversal of neurologic effects following oral and subcutaneous administration of rOPINIRole; tolerance to central effects was not apparent during chronic oral treatment (4 days) (Eden et al, 1991). In contrast, tolerance to hypotensive effects of rOPINIRole (related to peripheral D2 activity) has been evident after 1 week of oral administration, and is attributed to a compensatory increase in basal sympathetic tone as opposed to down-regulation of peripheral D2 receptors (Parker et al, 1994).
    2) APOMORPHINE: Apomorphine has been shown to improve motor function in animal models of Parkinson disease. Apomorphine attenuates the motor deficits induced by lesions in the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyly-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates (Prod Info APOKYN(R) subcutaneous injection, 2009).

References

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    27) Product Information: APOKYN(R) subcutaneous injection, apomorphine HCl subcutaneous injection. Ipsen Developments Limited, Slough, Berkshire, SL1 3XE, United Kingdom, 2009.
    28) Product Information: APOKYN(R) subcutaneous injection, apomorphine HCl subcutaneous injection. US WorldMeds, LLC (per DailyMed), Louisville, KY, 2015.
    29) Product Information: NEUPRO transdermal patch, rotigotine transdermal patch. UCB, Inc. (Per Manufacturer), Smyrna, GA, 2012.
    30) Product Information: NEUPRO(R) transdermal patch, rotigotine transdermal patch. Schwarz Pharma,LLC, Mequon, WI, 2004.
    31) Product Information: NEUPRO(R) transdermal system patch, rotigotine transdermal system patch. UCB, Inc. (per FDA), Smyrna, GA, 2015.
    32) Product Information: REQUIP XL(R) oral extended-release tablets, ropinirole oral extended-release tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2014.
    33) Product Information: REQUIP(R) oral tablets, ropinirole hcl oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2006.
    34) Product Information: REQUIP(R) oral tablets, ropinirole oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2014.
    35) Product Information: benztropine mesylate IV, IM injection, benztropine mesylate IV, IM injection. West-ward Pharmaceutical Corp, Eatontown, NJ, 2009.
    36) Product Information: diphenhydramine hcl injection, diphenhydramine hcl injection. Bioniche Pharma USA,LLC, Lake Forest, IL, 2006.
    37) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    38) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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