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PRAMIPEXOLE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pramipexole and talipexole are selective non-ergot, alpha-2/dopamine D2 agonists, with some 5-HT3 blocking properties.

Specific Substances

    A) PRAMIPEXOLE
    1) (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)
    2) benzothiazole dihydrochloride monohydrate
    3) pramepexol
    4) SUD919CL2Y
    5) U-98528E
    6) Molecular Formula: C10-H17-N3-S
    7) CAS 104632-26-0 (pramipexole)
    8) CAS 104632-25-9 (pramipexole dihydrochloride)
    TALIPEXOLE
    1) 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-
    2) thiazolo(4,5-d)azepine dihydrochloride
    3) Alefexole
    4) B-HT 920
    5) CAS 101626-70-4 (talipexole)
    6) CAS 36085-73-1 (talipexole dihydrochloride)

    1.2.1) MOLECULAR FORMULA
    1) PRAMIPEXOLE DIHYDROCHLORIDE: C10H17N3S x 2HCl x H2O (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info MIRAPEX(R) oral tablets, 2008)

Available Forms Sources

    A) FORMS
    1) Pramipexole is available in the United States as 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, and 1.5 mg tablets, and 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, and 4.5 mg extended-release tablets (Prod Info MIRAPEX ER(R) oral extended-release tablets, 2014; Prod Info MIRAPEX(R) oral tablets, 2008).
    B) USES
    1) Pramipexole is used in the treatment of signs and symptoms of idiopathic Parkinson's disease. It is also indicated for the treatment of moderate to severe Restless Legs Syndrome (Prod Info MIRAPEX(R) oral tablets, 2008).
    2) Talipexole is also under investigation for the treatment of schizophrenia (S Sweetman , 2001; S Budavari , 2001).

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: Pramipexole is a dopamine agonist. It is used to treat the signs and symptoms of Parkinson's disease and Restless Leg Syndrome.
    B) PHARMACOLOGY: Pramipexole is a non-ergot derived selective dopamine (D2/D3) receptor agonist. Therapeutic effect is likely due to increased dopaminergic neuron firing in the substantia nigra and striatum.
    C) TOXICOLOGY: Excessive dopamine agonist effects can cause lethargy and hallucinations.
    D) EPIDEMIOLOGY: Exposures are uncommon and life-threatening toxicity has not been reported with overdose.
    E) WITH THERAPEUTIC USE
    1) Adverse effects have included syncope (possibly due to orthostatic hypotension), somnolence, dizziness, extrapyramidal effects, nausea and vomiting, sweating, loss of color vision, peripheral edema and pallor. Auditory and visual hallucinations have also been reported.
    F) WITH POISONING/EXPOSURE
    1) There is little information on overdose in humans. Tachycardia, vomiting, lethargy, and drowsiness have been reported after overdose.
    0.2.20) REPRODUCTIVE
    A) Pramipexole is classified as FDA pregnancy category C. One case report described a woman who was treated with pramipexole during her pregnancy and delivered a healthy infant. In rat studies, pramipexole inhibited implantation, increased embryo resorption, and lowered prolactin levels. Single-dose rat studies have shown that pramipexole is excreted into breast milk of lactating rats. In rat fertility studies, pramipexole exposure resulted in inhibited implantation and prolonged estrous cycles, inhibited implantation, and reduced serum concentrations of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) No routine laboratory studies are necessary unless otherwise clinically indicated.
    C) ECG, serum electrolytes, salicylate, and acetaminophen concentrations should be obtained after deliberate overdose.
    D) Lab analysis should be directed towards ruling out more serious ingestions and conditions.
    E) Pramipexole concentrations are generally not available and are not clinically useful in guiding therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care is sufficient in nearly all patients. Antiemetics should be given if nausea and vomiting occurs. Investigation should be undertaken to assess for possibility of co-ingestants that may complicate the clinical course.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care remains the mainstay of treatment. Patients with co-ingestants causing respiratory depression or loss of airway reflexes should be intubated. Hypotension is not expected but should be treated with IV fluids and pressors if necessary. Patients with severe toxicity have likely ingested other substances.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is not indicated, as severe toxicity is not expected even in large overdoses.
    2) HOSPITAL: Activated charcoal, orogastric lavage, and whole bowel irrigation are not indicated in pramipexole overdose. Each method carries some risk, and pramipexole overdoses are usually benign. Consider activated charcoal if more toxic agents may be involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary unless co-ingestants that cause respiratory depression are present.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) Enhanced elimination is not indicated due to mild toxicity in overdose and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic after inadvertent ingestions may be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions or who are symptomatic should be referred to a healthcare facility. Those without significant signs and symptoms can likely be discharged after a 6-hour observation period.
    3) ADMISSION CRITERIA: Patients with severe CNS depression, and/or co-ingestions of other more toxic symptoms may require admission. In general, patients will be asymptomatic within 24 to 48 hours.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) The main pitfall is failure to recognize co-ingestion of more toxic substances, or attributing symptoms of a more serious illness to pramipexole use.
    I) PHARMACOKINETICS
    1) Rapid absorption occurs after oral dosing. Peak concentrations are reached at about 2 hours after ingestion. Bioavailability is more than 90%. Volume of distribution is about 400 L, and only 15% is bound to plasma proteins. Pharmacokinetics are linear over the clinical dose range. Its terminal half-life is about 8 hours in healthy young volunteers; terminal half-life can increase to 12 hours in the elderly. Urinary excretion is the major route of elimination; almost all of the drug is excreted unchanged.
    J) PREDISPOSING CONDITIONS
    1) Advanced age can lead to decreased renal elimination and prolonged course if toxicity occurs.
    K) DIFFERENTIAL DIAGNOSIS
    1) Non-toxicologic condition, ergoline derivative overdose.

Range Of Toxicity

    A) TOXICITY: Doses up to 11 mg for 2 days reported with only mild tachycardia developing. THERAPEUTIC: ADULT - Initial 0.125 mg three times daily increased weekly to 4.5 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Pramipexole is a dopamine agonist. It is used to treat the signs and symptoms of Parkinson's disease and Restless Leg Syndrome.
    B) PHARMACOLOGY: Pramipexole is a non-ergot derived selective dopamine (D2/D3) receptor agonist. Therapeutic effect is likely due to increased dopaminergic neuron firing in the substantia nigra and striatum.
    C) TOXICOLOGY: Excessive dopamine agonist effects can cause lethargy and hallucinations.
    D) EPIDEMIOLOGY: Exposures are uncommon and life-threatening toxicity has not been reported with overdose.
    E) WITH THERAPEUTIC USE
    1) Adverse effects have included syncope (possibly due to orthostatic hypotension), somnolence, dizziness, extrapyramidal effects, nausea and vomiting, sweating, loss of color vision, peripheral edema and pallor. Auditory and visual hallucinations have also been reported.
    F) WITH POISONING/EXPOSURE
    1) There is little information on overdose in humans. Tachycardia, vomiting, lethargy, and drowsiness have been reported after overdose.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Decreased blood pressure (80/50 mmHg) was reported in a 17-month-old child following the ingestion of one 1.0 mg pramipexole tablet (Hack et al, 1999).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Increased pulse rate (138 beats/min) with normal ECG has been reported in a 17-month-old child following the ingestion of 1 mg pramipexole (Hack et al, 1999) and an increased pulse (100 to 120 beats/min) was reported in an adult following 2 days of ingestion of 11 mg/day of pramipexole (Prod Info Mirapex(TM), pramipexole, 1999).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) A 72-year-old male parkinsonian patient developed dose-related loss of color vision when pramipexole was added to his regimen. Within 2 weeks of drug initiation, he complained of selective loss of color perception and temporary diplopia at a pramipexole dose of 0.18 mg three times daily. An increase in pramipexole to 0.7 mg/kg three times daily resulted in a total loss of color vision within a week, which improved somewhat when the dose was subsequently lowered again. Full color vision returned when the drug was discontinued (Muller et al, 2003).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) PRAMIPEXOLE: Syncope, possibly related to orthostatic hypotension, has been occasionally reported as an adverse effect in clinical trials (Goetz et al, 1994).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) PRAMIPEXOLE: Pulse rate increased to between 100 and 120 beats/minute in an adult who ingested 11 mg/day (2 to 3 times the recommended dose) of pramipexole for 2 days (Prod Info MIRAPEX(R) oral tablets, 2008).
    b) PRAMIPEXOLE: Increased pulse rate (138 beats/min) with normal ECG has been reported in a 17-month-old child following the ingestion of 1 mg pramipexole (Hack et al, 1999).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) INCIDENCE
    1) Up to 30% of patients in clinical trials have experienced drowsiness, fatigue or dizziness as adverse effects, which are possibly related to dose (Ohmori et al, 1993; Goetz et al, 1994; Anon, 1996; Mizuno et al, 1993).
    a) A letter has been issued by the U.S. Food and Drug Administration cautioning health care providers about the possibility of patients falling asleep during activities of daily living while taking therapeutic pramipexole. Doses of pramipexole above 1.5 mg/day are commonly associated with somnolence ((Anon, 1999)).
    2) SEVERITY: Four of 13 patients were withdrawn from a talipexole study due to severity of sedation and dizziness (Goetz et al, 1994). Sudden onset of sleep can occur, with no prior feeling of drowsiness; this may occur with no warning at any time during therapy. Reduction of dose may alleviate this adverse effect (S Sweetman , 2001).
    b) PRAMIPEXOLE: In clinical trials, other CNS effects (insomnia, somnolence, hallucinations, and confusion ) have also been reported in greater than 5% of patients with therapeutic use (Prod Info MIRAPEX(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) 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) CASE REPORT: Lethargy was reported in a 17-month-old child following the ingestion of one pramipexole 1 mg tablet. The child was lethargic but arousable, and otherwise had a normal neurologic examination (Hack et al, 1999).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) INCIDENCE
    1) In clinical trials, extrapyramidal syndrome has been reported in greater than 5% of patients with therapeutic use (Prod Info MIRAPEX(R) oral tablets, 2008; Wetzel & Benkert, 1993). Oral dyskinesia was observed in one of 15 schizophrenic patients in one study (Ohmori et al, 1993).
    2) PRAMIPEXOLE: Dyskinesia (47 of 260 patients) was the most frequently reported neurological effect by patients during clinical trials (Prod Info MIRAPEX(R) oral tablets, 2008).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERKINESIA
    a) MARMOSETS: In normosensitive animals, higher doses of talipexole (80-160 mcg/kg IP) caused increased motor activity, whereas lower doses (20 mcg/kg IP) caused a decrease in motor activity (Irifune et al, 1993).
    2) SOMNOLENCE
    a) When monkeys were administered anti-tremor doses of talipexole, sedative effects were observed (Kohno et al, 1997).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) INCIDENCE
    1) PRAMIPEXOLE: Nausea is a frequent complaint of patients taking pramipexole (Prod Info MIRAPEX(R) oral tablets, 2008).
    2) Nausea and gastrointestinal discomfort have been reported as adverse effects in clinical trials of talipexole in approximately 10% of patients (Mizuno et al, 1993; Anon, 1996; Ohmori et al, 1993).
    b) 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).
    c) CASE REPORT: Following an unintentional ingestion of one pramipexole 1.0 mg tablet, a 17-month-old child vomited within an hour (Hack et al, 1999).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) PRAMIPEXOLE: In clinical trials, constipation was reported in more than 5% of patients with Parkinson's disease receiving pramipexole (Prod Info MIRAPEX(R) oral tablets, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Pallor and sweating have been reported in clinical studies as adverse events (Goetz et al, 1994).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Mild to severe idiosyncratic peripheral edema was documented in 17 out of 300 patients (5.7%) taking pramipexole whose records were reviewed in a retrospective case series. The average time to onset of the side-effect was 2.6 +/- 3.6 months after starting the drug (range: 0.25-11 months). The mean dose of pramipexole at onset was 1.7 +/- 1.0 mg/d (range: 0.75-3 mg/d). In all 17 cases, the peripheral edema abated when the drug was discontinued (Tan & Ondo, 2000).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) PRAMIPEXOLE: A single case of rhabdomyolysis was reported by the manufacturer in a 49-year-old man with advanced Parkinson's. CPK was elevated to 10,631 International Units/L with resolution of symptoms upon drug cessation (Prod Info MIRAPEX(R) oral tablets, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Pramipexole is classified as FDA pregnancy category C. One case report described a woman who was treated with pramipexole during her pregnancy and delivered a healthy infant. In rat studies, pramipexole inhibited implantation, increased embryo resorption, and lowered prolactin levels. Single-dose rat studies have shown that pramipexole is excreted into breast milk of lactating rats. In rat fertility studies, pramipexole exposure resulted in inhibited implantation and prolonged estrous cycles, inhibited implantation, and reduced serum concentrations of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    B) ANIMAL STUDIES
    1) RATS: Teratogenic effect could not be adequately assessed due to the early loss of embryos (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    2) RABBIT: In rabbit studies, embryo-fetal development was not adversely affected at pramipexole doses up to 10 mg/kg/day (AUC 71 times that in humans at the MRHD) during organogenesis (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009)
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified pramipexole as FDA pregnancy category C (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    B) LACK OF EFFECT
    1) CASE REPORT: A healthy infant was born by caesarean delivery to a woman with Parkinson disease who took only pramipexole to control her symptoms during pregnancy (Mucchiut et al, 2004).
    C) ANIMAL STUDIES
    1) RATS: Implantation was inhibited when rats were given pramipexole at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose (MRHD) on a mg/m(2) basis). When pregnant rats were exposed to pramipexole at a dose of 1.5 mg/kg/day (AUC at this dose about 4 times of that in humans at the MRHD) during the period of organogenesis (gestation days 7 through 16), there was a high incidence of total resorption of embryos. Pramipexole lowers prolactin levels and prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). When rats were exposed to pramipexole at doses of 0.5 mg/kg/day (about equivalent to the MRHD on a mg/m(2) basis) throughout the latter part of gestation and lactation, postnatal growth was inhibited in the offspring. (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    2) RABBITS: Embryo-fetal development was not adversely affected at pramipexole doses up to 10 mg/kg/day (AUC 71 times that in humans at the MRHD) during organogenesis (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No reports describing the use of pramipexole during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. However, there are studies that report inhibition of prolactin secretion in humans and rats resulting from pramipexole (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    B) ANIMAL STUDIES
    1) RATS: In a single-dose, radiolabeled study conducted in lactating rats, pramipexole-related components were present in rat milk at concentrations 3 to 6 times higher than that in plasma at equivalent time points (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Administration of pramipexole to rats at a dose of 2.5 mg/kg/day (5 times the recommended human dose on a mg/m(2) basis) resulted in prolonged estrous cycles, inhibited implantation, and reduced serum concentrations of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info Mirapex(R) oral tablets, 2009).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) PRAMIPEXOLE - In a 2-year carcinogenicity study, pramipexole was administered to mice at up to 11 times the highest recommended human dose and administered to rats at up to 12.5 times the AUC in humans receiving 1.5 mg 3 times daily; no significant increases in tumors were reported (Prod Info Mirapex(TM), pramipexole, 1999).

Genotoxicity

    A) PRAMIPEXOLE - No mutagenicity or clastogenicity was reported in a battery of assays for pramipexole; tests included the in vitro Ames assay, V79 gene mutation assay for HGPRT mutants, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus assay (Prod Info Mirapex(TM), pramipexole, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) No routine laboratory studies are necessary unless otherwise clinically indicated.
    C) ECG, serum electrolytes, salicylate, and acetaminophen concentrations should be obtained after deliberate overdose.
    D) Lab analysis should be directed towards ruling out more serious ingestions and conditions.
    E) Pramipexole concentrations are generally not available and are not clinically useful in guiding therapy.

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) Patients with severe CNS depression, and/or co-ingestions of other more toxic symptoms may require admission. In general, patients will be asymptomatic within 24 to 48 hours.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic after inadvertent ingestions may be managed at home.
    B) PRAMIPEXOLE: 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. The authors suggested that children with unintentional ingestions of less than 1 mg of pramipexole and minor effects may be managed at home with telephone follow-up (DesLauriers et al, 2008).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions or who are symptomatic should be referred to a healthcare facility. Those without significant signs and symptoms can likely be discharged after a 6-hour observation period.

Monitoring

    A) Monitor vital signs and mental status.
    B) No routine laboratory studies are necessary unless otherwise clinically indicated.
    C) ECG, serum electrolytes, salicylate, and acetaminophen concentrations should be obtained after deliberate overdose.
    D) Lab analysis should be directed towards ruling out more serious ingestions and conditions.
    E) Pramipexole concentrations are generally not available and are not clinically useful in guiding therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not indicated, as severe toxicity is not expected even in large overdoses.
    6.5.2) PREVENTION OF ABSORPTION
    A) Activated charcoal, orogastric lavage, and whole bowel irrigation are not indicated in pramipexole overdose. Each method carries some risk, and pramipexole overdoses are usually benign.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) No routine laboratory studies are necessary unless otherwise clinically indicated.
    3) ECG, serum electrolytes, salicylate, and acetaminophen concentrations should be obtained after deliberate overdose.
    4) Lab analysis should be directed towards ruling out more serious ingestions and conditions.
    5) Pramipexole concentrations are generally not available and are not clinically useful in guiding therapy.
    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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Enhanced elimination is not indicated due to mild toxicity in overdose and large volume of distribution (about 400 L).

Range Of Toxicity

Summary

    A) TOXICITY: Doses up to 11 mg for 2 days reported with only mild tachycardia developing. THERAPEUTIC: ADULT - Initial 0.125 mg three times daily increased weekly to 4.5 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) PARKINSON'S DISEASE
    1) PRAMIPEXOLE - Pramipexole should be titrated gradually with a starting dose of 0.375 milligrams/day orally given in three divided doses and should not be increased more frequently than every 5 to 7 days; maintenance therapy - 1.5 to 4.5 milligrams/day, in three equally divided doses (Prod Info MIRAPEX(R) oral tablets, 2008).
    B) RESTLESS LEGS SYNDROME
    1) PRAMIPEXOLE - The recommended initial dose is 0.125 milligram orally once daily, given 2 to 3 hours before bedtime. Four to seven days after the initial dose, the dose may be increased to 0.25 milligram once daily, and then to 0.5 milligram once daily 4 to 7 days later, if needed (Prod Info MIRAPEX(R) oral tablets, 2008).
    7.2.2) PEDIATRIC
    A) PRAMIPEXOLE - Safety and efficacy of pramipexole in pediatric patients has not been established (Prod Info MIRAPEX(R) oral tablets, 2008).

Maximum Tolerated Exposure

    A) CHILDREN
    1) PRAMIPEXOLE: A 17-month-old girl was reported to have spontaneous vomiting within an hour of a 1 milligram inadvertent overdose. In the ED she was reported to be lethargic, but arousable. Blood pressure was reported to be 80/50 mmHg and pulse rate was 138 beats/minute. Neurologic examination, other than lethargy, and ECG were reportedly normal (Hack et al, 1998).
    2) PRAMIPEXOLE: 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).
    B) ADULT
    1) PRAMIPEXOLE: Pulse rate increased to between 100 and 120 beats/minute in a schizophrenic patient who took 11 milligrams/day of pramipexole for 2 days. No other adverse effects were reported and blood pressure remained stable (Prod Info MIRAPEX(R) oral tablets, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE
    1) LD50- (ORAL)RAT:
    a) greater than 800 mg/kg (RTECS , 2002)
    B) TALIPEXOLE DIHYDROCHLORIDE
    1) LD50- (ORAL)MOUSE:
    a) 455 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)RAT:
    a) 403 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DOPAMINE D2 AGONIST - PRAMIPEXOLE is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, yet with higher specificity for D3 receptors (Prod Info MIRAPEX(R) oral tablets, 2008). The precise mechanism of action as it relates to the treatment of Parkinson's disease is unknown, but may stimulate the dopamine receptors in the striatum, which is supported by electrophysiologic studies in animals.
    B) Talipexole, a dopamine-2(D2) receptor autoagonist, was developed primarily for the treatment of Parkinson's disease and schizophrenia (Wetzel & Benkert, 1993; Mizuno et al, 1993). Dopaminergic autoagonists stimulate presynaptic dopamine receptors, resulting in a decrease in dopamine turnover and synthesis due to a negative feedback mechanism; inhibition of dopaminergic neuronal firing is observed (Ohmori et al, 1993; Wetzel & Benkert, 1993; Goetz et al, 1994). Irifune et al (1993) have demonstrated selective dopamine D2 receptor agonist properties and postsynaptic agonist properties of talipexole in marmoset studies.
    C) Investigations have demonstrated partial or full agonist properties of the drug at both presynaptic and postsynaptic D2 receptors (Ohmori et al, 1993; Wetzel & Benkert, 1993). This suggests the drug may be more appropriately labeled a nonselective D2 receptor agonist. Talipexole also possesses alpha-2 adrenergic agonist properties, especially at higher doses, similar to clonidine (Wetzel & Benkert, 1993; Sanchez-Merino et al, 1990). No agonist activity at D1 receptor sites has been demonstrated (Ohmori et al, 1993).
    D) Pramipexole has been shown to stimulate dopamine receptors in the striatum. Electrophysiologic studies in animals have shown that pramipexole activates dopamine receptors in the striatum and the substantia nigra, thus influencing striatal neuronal firing rates (Prod Info Mirapex(TM), pramipexole, 1999).
    E) Nishio et al (1996) have demonstrated, in rat studies, moderate displacement activity of (3)H-GR 65630 binding to 5-HT3 receptors in both rat cortical and intestinal membrane fractions following talipexole dosing. It was also found to significantly inhibit 5-HT3 receptor-mediated activity in guinea-pig ileum or atrium. These authors concluded that talipexole may act as a moderate antagonist on 5-HT3 receptors in both brain and intestinal tissues (Nishio et al, 1996).
    F) Talipexole has demonstrated a lesser influence on serotonin-mediated responses than does equipotent antiparkinson doses of bromocriptine in rat studies. Talipexole was shown to possess 5-HT3 receptor blocking activity, with a potency about 1/10th of its D2 receptor agonistic effect. Fewer emetic adverse effects are seen, possibly because emetic responses triggered by D2 receptor stimulation may secondarily stimulate an increase in abdominal afferent vagal activity, which in turn may be weakened by the 5-HT3 receptor antagonistic property of talipexole (Minami et al, 1997).
    1) When talipexole was administered in anti-tremor doses to monkeys, no emetic behaviors were observed, but sedative effects were seen. When bromocriptine was given in anti-tremor doses, oral movement, salivation and vomiting were observed, but no marked sedative effects were seen (Kohno et al, 1997).

Physicochemical

Physical Characteristics

    A) PRAMIPEXOLE DIHYDROCHLORIDE is a white to off-white powder substance with a melting range of 296 to 301 degrees C, with decomposition. It is greater than 20% soluble in water, about 8% soluble in methanol, about 0.5% soluble in ethanol, and practically insoluble in dichloromethane (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info MIRAPEX(R) oral tablets, 2008).

Molecular Weight

    A) PRAMIPEXOLE DIHYDROCHLORIDE: 302.26 (Prod Info MIRAPEX ER(R) extended release oral tablets, 2010; Prod Info MIRAPEX(R) oral tablets, 2008)
    B) TALIPEXOLE DIHYDROCHLORIDE: 282.2 (S Budavari , 2001)

References

General Bibliography

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