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BROMOCRIPTINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bromocriptine is an ergoline derivative and selective dopamine agonist with a high affinity for the D2 receptor site.

Specific Substances

    A) BROMOCRIPTINE
    1) 2-bromo-alpha-ergocryptine
    2) 2-Bromoergocryptine monomethane sulfonate
    3) Bromocriptine mesylate
    4) Bromocriptine methanesulphonate
    5) CB-154
    LISURIDE (synonym)
    1) Lisuride maleate (synonym)
    2) Methylergol carbamide maleate
    3) CAS 18016-80-3 (lisuride)
    4) CAS 19875-60-6 (lisuride maleate)

    1.2.1) MOLECULAR FORMULA
    1) C32H40BrN5O5-CH4SO3

Available Forms Sources

    A) FORMS
    1) Bromocriptine mesylate is available as 0.8 mg tablets (Prod Info CYCLOSET(R) oral tablets, 2010) and as 2.5 mg scored tablets and 5 mg capsules (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    B) USES
    1) Bromocriptine is indicated for treatment of dysfunctions associated with hyperprolactinemia, acromegaly to reduce serum growth hormone, and for idiopathic or postencephalitic Parkinson's disease (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    2) Bromocriptine is also indicated as adjunctive therapy to diet and exercise for improvement of glycemic control in adult patients with type 2 diabetes mellitus (Prod Info CYCLOSET(R) oral tablets, 2010).
    3) Bromocriptine mesylate is no longer indicated for the treatment of suppression of physiological post partum lactation, both in the United States and in Canada. The FDA determined that the risk that bromocriptine may cause a serious adverse effect in post partum women which was not acceptable (Anon, 1994).

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: Bromocriptine is indicated for the treatment of hyperprolactinemia-associated dysfunctions (including amenorrhea, infertility, or hypogonadism), acromegaly, type 2 diabetes, and for idiopathic or post-encephalitic Parkinson's disease.
    B) PHARMACOLOGY: Bromocriptine is an ergoline derivative and selective dopamine and serotonin agonist with a high affinity for D2, 5-HT2A, and 5-HT2B receptors. It is also a D1 receptor antagonist. Reduced tonic stimulation of dopaminergic D2 receptors located on intrastriatal cholinergic neurons are the most likely cause of the parkinsonian symptoms. Bromocriptine occupies dopaminergic receptors in the pituitary gland to inhibit prolactin secretion. Dopamine agonist activity also lowers post-prandial and fasting glucose levels.
    C) TOXICOLOGY: Dopaminergic activity is believed to cause peripheral vasoconstriction akin to ergotism.
    D) EPIDEMIOLOGY: Acute overdoses are rarely reported. Adverse drug reactions are common, especially at time of drug initiation.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported effects, with an incidence of at least 5%, following therapeutic administration include nausea, vomiting, constipation, orthostatic hypotension, headache, dizziness, fatigue, and lightheadedness.
    2) INFREQUENT: Other adverse effects that may occur less frequently include abdominal cramps, anorexia, cardiac dysrhythmias, digital vasospasm, dry mouth, dyskinesias, and myoclonus. Coronary thrombosis, hypertension, myocardial infarction, seizures, and strokes have been reported in several post-partum women who had been taking bromocriptine for lactation suppression.
    3) Pleural and pulmonary fibrosis, pleural effusion, retroperitoneal fibrosis, and pleuritic chest pain have all been reported in association with chronic high-dose (20 to 30 mg/day) bromocriptine therapy, although in the majority of cases a specific causal relationship has not been established.
    4) WITHDRAWAL: Neuroleptic malignant syndrome has been rarely reported following rapid dose reduction or abrupt withdrawal of bromocriptine therapy.
    F) WITH POISONING/EXPOSURE
    1) Commonly reported signs and symptoms of overdose are nausea, vomiting, constipation, diaphoresis, dizziness, severe hypotension, malaise, confusion, lethargy, drowsiness, hallucinations, and repetitive yawning.
    0.2.3) VITAL SIGNS
    A) Hypothermia has been reported in patients following bromocriptine administration.
    0.2.20) REPRODUCTIVE
    A) Bromocriptine mesylate is classified as FDA pregnancy category B. Congenital abnormalities have occurred following maternal bromocriptine therapy, but the incidences of malformation and spontaneous abortion are not considered greater than that reported for spontaneous occurrences in the population at large. Bromocriptine inhibits lactation and stroke has been reported in nursing mothers during postmarketing use of the drug. Therefore, bromocriptine is contraindicated for use in nursing mothers.

Laboratory Monitoring

    A) Monitor blood pressure and ECG in symptomatic patients. Monitor for CNS signs of dyskinesias or seizures.
    B) Monitor serum electrolytes and acid/base balance in patients with prolonged vomiting or seizures.
    C) Bromocriptine plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Control agitation and confusion with benzodiazepines. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe CNS depression or respiratory failure.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) Due to the high protein binding of bromocriptine (90% to 96%), hemodialysis is unlikely to be of benefit.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, who remains asymptomatic, can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    H) PITFALLS
    1) Be mindful of drug-drug interactions. Bromocriptine is metabolized via cytochrome P450 3A4 enzymes. When managing a suspected bromocriptine overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Approximately 65% to 95% of bromocriptine mesylate is absorbed after oral administration and after extensive gastrointestinal and hepatic first-pass metabolism, 7% of the dose reaches the systemic circulation. Protein binding is 90% to 96%. Volume of distribution is 61 liters. Extensively metabolized in the liver by the CYP3A4 pathway with approximately 93% of the absorbed dose undergoing first-pass metabolism. Approximately 2% to 6% of oral dose of bromocriptine mesylate is excreted via the urine, and elimination half-life has reportedly ranged from 6 to 50 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other dopamine agonists including ergot-derived (eg, cabergoline and pergolide) and non-ergot-derived (eg, ropinirole and pramipexole).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Bromocriptine overdoses up to 25 mg in children have resulted in vomiting and drowsiness. A lisuride ingestion of 1 mg in a toddler resulted in respiratory acidosis and persistent hypotension. The child recovered with symptomatic and supportive care.
    B) THERAPEUTIC USE: Varies by disease state in adults. ACROMEGALY: Bromocriptine: Usual dosage range of 20 to 30 mg daily; maximum dose of 100 mg daily. DIABETES MELLITUS TYPE 2: Bromocriptine: Usual dosage range is 1.6 to 4.8 mg once daily; maximum daily dose is 4.8 mg. HYPERPROLACTINEMIA: Bromocriptine: Usual dosage range of 2.5 to 15 mg daily. PARKINSON'S DISEASE: Bromocriptine: Initial dose is 1.25 mg twice daily, increasing by 2.5 mg daily every 14 to 28 days as needed; maximum dose of 100 mg/day. CHILDREN (11 to 15 years): For prolactinoma, the bromocriptine maintenance dosage regimen is 2.5 to 10 mg daily, based on limited data from clinical trials.

Clinical Effects

Summary Of Exposure

    A) USES: Bromocriptine is indicated for the treatment of hyperprolactinemia-associated dysfunctions (including amenorrhea, infertility, or hypogonadism), acromegaly, type 2 diabetes, and for idiopathic or post-encephalitic Parkinson's disease.
    B) PHARMACOLOGY: Bromocriptine is an ergoline derivative and selective dopamine and serotonin agonist with a high affinity for D2, 5-HT2A, and 5-HT2B receptors. It is also a D1 receptor antagonist. Reduced tonic stimulation of dopaminergic D2 receptors located on intrastriatal cholinergic neurons are the most likely cause of the parkinsonian symptoms. Bromocriptine occupies dopaminergic receptors in the pituitary gland to inhibit prolactin secretion. Dopamine agonist activity also lowers post-prandial and fasting glucose levels.
    C) TOXICOLOGY: Dopaminergic activity is believed to cause peripheral vasoconstriction akin to ergotism.
    D) EPIDEMIOLOGY: Acute overdoses are rarely reported. Adverse drug reactions are common, especially at time of drug initiation.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported effects, with an incidence of at least 5%, following therapeutic administration include nausea, vomiting, constipation, orthostatic hypotension, headache, dizziness, fatigue, and lightheadedness.
    2) INFREQUENT: Other adverse effects that may occur less frequently include abdominal cramps, anorexia, cardiac dysrhythmias, digital vasospasm, dry mouth, dyskinesias, and myoclonus. Coronary thrombosis, hypertension, myocardial infarction, seizures, and strokes have been reported in several post-partum women who had been taking bromocriptine for lactation suppression.
    3) Pleural and pulmonary fibrosis, pleural effusion, retroperitoneal fibrosis, and pleuritic chest pain have all been reported in association with chronic high-dose (20 to 30 mg/day) bromocriptine therapy, although in the majority of cases a specific causal relationship has not been established.
    4) WITHDRAWAL: Neuroleptic malignant syndrome has been rarely reported following rapid dose reduction or abrupt withdrawal of bromocriptine therapy.
    F) WITH POISONING/EXPOSURE
    1) Commonly reported signs and symptoms of overdose are nausea, vomiting, constipation, diaphoresis, dizziness, severe hypotension, malaise, confusion, lethargy, drowsiness, hallucinations, and repetitive yawning.

Vital Signs

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

Heent

    3.4.3) EYES
    A) OVERDOSE may result in mydriasis.
    1) MYDRIASIS was reported in two children who overdosed on bromocriptine (Vermund et al, 1984).
    B) BITEMPORAL HEMIANOPSIA has occurred when bromocriptine was used to induce pregnancy in patients with pituitary adenomas (Grant & Schuman, 1993). During the twenty-eighth week of pregnancy a 23-year-old woman with a pituitary adenoma was treated with bromocriptine, the patient developed deterioration of the visual field and bitemporal defects. Sight was restored by surgical decompression of the chiasma (VanDalen & Greve, 1977)
    C) MYOPIA has been reported in a patient following bromocriptine therapy, which reversed after bromocriptine was stopped (Grant & Schuman, 1993).
    D) DECREASED VISION: Bilateral visual acuity loss occurred in a 25-year-old woman following bromocriptine therapy 2.5 mg twice daily (2 cycles, 17 days per cycle) for ovulation induction. Upon discontinuing bromocriptine, prolactin levels increased immediately. Pregnancy was terminated by C-section at the thirty-ninth week with delivery of a normal fetus. Bromocriptine was reinstituted 3 days postoperatively and visual complaints disappeared (Corbey et al, 1977).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASAL CONGESTION has been reported in 4% of patients administered bromocriptine for treatment of acromegaly (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) APTYALISM: Dry mouth has been reported in 4% of patients administered bromocriptine for treatment of acromegaly (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Severe hypotension has been reported following bromocriptine overdose (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) CASE REPORT/BROMOCRIPTINE: Hypotension and shallow breathing were reported in a child who accidentally ingested about 25 mg of bromocriptine (Vermund et al, 1984).
    c) CASE REPORT/LISURIDE: A 21-month-old child developed respiratory acidosis (pH 7.32, pCO2 48 mmHg, pO2 86 mmHg, and HCO3 24 mEq/L), tachycardia (96 bpm), tachypnea (22 breaths per minute), a reduced level of consciousness (Glasgow Coma Scale score of 8), and persistent hypotension (76/52 mmHg) after inadvertent ingestion of 1 mg lisuride maleate tablets (approximately 0.075 mg/kg). With symptomatic and supportive therapy, including vasopressor administration, the patient completely recovered and was discharged approximately 4 days postingestion (Alahmadi & Mujawar, 2013).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Cardiac dysrhythmias have been reported with therapeutic use (Miller et al, 1989).
    C) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/LISURIDE: A 21-month-old child developed respiratory acidosis (pH 7.32, pCO2 48 mmHg, pO2 86 mmHg, and HCO3 24 mEq/L), tachycardia (96 bpm), tachypnea (22 breaths per minute), a reduced level of consciousness (Glasgow Coma Scale score of 8), and persistent hypotension (76/52 mmHg) after inadvertent ingestion of 1 mg lisuride maleate tablets (approximately 0.075 mg/kg). With symptomatic and supportive therapy, including vasopressor administration, the patient completely recovered and was discharged approximately 4 days postingestion (Alahmadi & Mujawar, 2013).
    D) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) Postural/orthostatic hypotension was reported in 6% of patients who were treated with bromocriptine mesylate for acromegaly (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    E) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension, myocardial infarction, seizures, and stroke have been rarely reported with bromocriptine use in postpartum women. Hypertension has occurred at the start of therapy; although, it may develop more commonly during the second week of therapy (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) In a prospective study of 1813 women, the use of bromocriptine was only associated with hypertension in those with a history of pregnancy-induced hypertension (Watson et al, 1989).
    F) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction has been reported in 17 postpartum women. Predisposing conditions were thought to include a history of pregnancy-induced hypertension or other vasospastic conditions, such as Raynaud's disease or migraine headaches (Ruch & Duhring, 1989).
    b) Three cases of myocardial infarction were reported in women using bromocriptine for lactation suppression. The first patient was a healthy 39-year-old woman with an uneventful pregnancy and delivery. She began bromocriptine immediately after childbirth and presented on postpartum day 12 with a numb left arm and paresthesias in the right hand. The second patient was a normal 25-year-old with an uneventful pregnancy and moderate postpartum hemorrhage. She left the hospital with a prescription for bromocriptine 2 days after delivery. On day 6, she presented with headache, shortness of breath and persistent crushing, retrosternal chest pain. The third patient was obese and her 2 previous pregnancies were complicated by hypertension. Her history also included a petit mal seizure and tobacco use. At two weeks postpartum, she began bromocriptine. At 22 days postpartum, she had a seizure and was started on carbamazepine. At 24 days postpartum, the patient had chest pain, collapsed, and expired 1 hour later (Hopp et al, 1996).
    G) PERIPHERAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) RAYNAUD'S PHENOMENON: Use of bromocriptine in the treatment of female infertility has been associated with digital vasospasm (Quagliarello & Barakat, 1987). It has not been established whether bromocriptine can be implicated as a definite cause of digital vasospasm.
    H) CORONARY ARTERY THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 35-year-old woman receiving bromocriptine for lactation suppression experienced a seizure and died the next day after experiencing chest pain . She had a past medical history of head trauma and seizures. She was taking bromocriptine 2.5 mg twice daily during her third postpartum week. Within 48 hours she experienced seizure activity. She was told in the emergency room to discontinue bromocriptine. The next day she died after complaining of chest pain. On autopsy, acute coronary thrombosis of the left main, left anterior descending and circumflex arteries was found. Her death was thought to be due to coronary artery vasospasm with subsequent thrombus formation (Loewe & Dragovic, 1998).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) FIBROSIS OF LUNG
    1) Pleural and pulmonary fibrosis, pleural effusion, retroperitoneal fibrosis, and pleuritic chest pain have all been reported in association with chronic high-dose (20 to 30 mg/day) bromocriptine therapy; however, in most cases, a causal relationship has not been definitely established (Rinne, 1981; McElvaney et al, 1988; Ward et al, 1987; Melmed & Braunstein, 1989; Anon, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Dyskinesia has been reported during postmarketing use of bromocriptine (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) INCIDENCE: In a comparison study of bromocriptine and cabergoline, dyskinesias occurred as adverse effects at similar frequencies (36%) with both drugs (Inzelberg et al, 1996).
    B) DROWSY
    1) WITH POISONING/EXPOSURE
    a) BROMOCRIPTINE: Malaise, drowsiness, confusion, and lethargy have been reported as overdose effects of bromocriptine (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) CASE REPORT/BROMOCRIPTINE: Following overdoses of bromocriptine in two children, the most notable symptom was lethargy with altered mental status. One child was also reported to have hyperreflexic lower extremities (Vermund et al, 1984).
    c) CASE REPORT/LISURIDE: A 21-month-old child developed respiratory acidosis (pH 7.32, pCO2 48 mmHg, pO2 86 mmHg, and HCO3 24 mEq/L), tachycardia (96 bpm), tachypnea (22 breaths per minute), a reduced level of consciousness (Glasgow Coma Scale score of 8), and persistent hypotension (76/52 mmHg) after inadvertent ingestion of 1 mg lisuride maleate tablets (approximately 0.075 mg/kg). With symptomatic and supportive therapy, including vasopressor administration, the patient completely recovered and was discharged approximately 4 days postingestion (Alahmadi & Mujawar, 2013).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported in 19% of patients with hyperprolactinemic indications who were receiving bromocriptine during clinical trials (Prod Info Parlodel(R) oral tablets, oral capsules, 2012)
    b) Headache, requiring treatment at medical facilities, has been reported (Gittelman, 1991; Kulig et al, 1991).
    D) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) Cerebral ischemia and stroke have been reported with bromocriptine therapy. In addition, 9 deaths have been reported in 31 stroke patients (Katz et al, 1985; Maurel et al, 1990). As a result, approval for bromocriptine use in suppression of postpartum lactation has been withdrawn as of September 1994 (Anon, 1994). Multiparity and age over 30 years are thought to be predisposing factors for cerebrovascular accidents. The proposed mechanism of bromocriptine-induced changes in the intravascular compartment creating hyperviscosity leading to thromboemboli, is supported by the elevated erythrocytosis and hematocrit noted in these patients (Katz et al, 1985). A fatal case of severe brain stem injury secondary to occlusion of the right internal carotid artery occurred in a 30-year-old woman taking bromocriptine 2.5 mg orally 3 times daily. Additionally, the patient exhibited pallor of the left forearm and hand. Arteriography showed occlusion of the humeral artery. The patient had a medical history which included smoking and obesity (Maurel et al, 1990).
    b) CEREBROVASCULAR ACCIDENTS (CVA) have occurred in postpartum women receiving bromocriptine. Multiparity and age over 30 years old were thought to be predisposing factors (Katz et al, 1985a) FDA, 1984).
    1) CASE REPORT: Postpartum use of bromocriptine was associated with the development of carotid and humeral artery thrombosis in a 30-year-old woman. Subsequent cerebral CT scan identified a hypodensity, indicating cerebral infarction. She died secondary to severe brain stem injury (Maurel et al, 1990a).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness, fatigue, and lightheadedness were reported in 17%, 7%, and 5% of patients, respectively, with hyperprolactinemic indications who received bromocriptine during clinical trials (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    2) WITH POISONING/EXPOSURE
    a) Sedation and dizziness have been reported as overdose effects of bromocriptine (Prod Info Parlodel(R) oral tablets, oral capsules, 2012; Vermund et al, 1984).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Thirty-eight cases of seizures were reported to the FDA by 1989 in women receiving bromocriptine to suppress lactation. Mean onset was 7 days postpartum (Gittelman, 1991).
    b) A 35-year-old woman receiving bromocriptine for lactation suppression experienced a seizure and died the next day after experiencing chest pain . She had a past medical history of head trauma and seizures. She was taking bromocriptine 2.5 mg twice daily during her third postpartum week. Within 48 hours she experienced seizure activity. She was told in the emergency room to discontinue bromocriptine. The next day she died after complaining of chest pain. On autopsy, acute coronary thrombosis of the left main, left anterior descending and circumflex arteries was found. Her death was thought to be due to coronary artery vasospasm with subsequent thrombus formation (Loewe & Dragovic, 1998).
    G) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: In a comparison study of cabergoline and bromocriptine in Parkinson's patients, bromocriptine therapy was associated with a 14% incidence of paresthesias (Inzelberg et al, 1996).
    H) MYOCLONUS
    1) WITH THERAPEUTIC USE
    a) Myoclonus has been reported in two neurologically impaired patients treated with bromocriptine for dystonia. Bromocriptine was discontinued and the myoclonus resolved in both patients (Buchman et al, 1987).
    I) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: PITUITARY APOPLEXY was reported in a 50-year-old woman with a pituitary adenoma, who presented with acromegaly. After a single oral dose of bromocriptine 2.5 mg the patient became hypotensive and complained of nausea, vomiting, diminished vision, and headache. It has not been clearly established that the apoplexy and bromocriptine are related (Shirataki et al, 1988).
    J) NEURALGIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Trigeminal neuralgic pain attacks lasting 5 hours were provoked in a patient with a pituitary tumor after a single oral dose of 1.25 mg bromocriptine (Ferrari et al, 1988).
    K) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, a neuroleptic-like malignant syndrome has been reported very rarely with rapid dose reduction or abrupt withdrawal of bromocriptine mesylate when used for Parkinson's disease (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) BROMOCRIPTINE WITHDRAWAL/CASE REPORT: A 74-year-old man on bromocriptine therapy 5 mg/day for 3 years to treat Parkinson disease presented to the emergency department with symptoms of neuroleptic malignant syndrome (NMS) 1 week after his bromocriptine was abruptly discontinued. At presentation his blood pressure was 163/104 mmHg and his heart rate was 113 bpm with sinus tachycardia on ECG. As he was admitted to medical service, he became somnolent, his mental status declined, severe muscle rigidity and autonomic dysfunction were observed, and he experienced visual hallucinations and agitation. His temperature elevated to 39 degrees C and lab analysis showed metabolic acidosis, AST 296 Units/L, ALT 64 Units/L, LDH 238 Units/L, CK 14,470 Units/L, and C-reactive protein 2.55 mg/dL. Infection was ruled out. He was treated with IV crystalloids and bicarbonates along with supportive therapy. Bromocriptine was restarted at 2.5 mg 4 times daily. Within 2 days of restarting bromocriptine, the muscle rigidity showed improvement. By day 11 of admission, his CK level had decreased to 36 U/L and his mental status and muscle rigidity both continued to improve. He was discharged with bromocriptine 3 times daily without recurrence of NMS (Wu et al, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) BROMOCRIPTINE: Nausea and vomiting have commonly occurred as adverse effects in clinical trials (Prod Info Parlodel(R) oral tablets, oral capsules, 2012; Prod Info CYCLOSET(R) oral tablets, 2010; Webster et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) BROMOCRIPTINE: Nausea and vomiting have occurred as overdose effects (Prod Info Parlodel(R) oral tablets, oral capsules, 2012; Vermund et al, 1984) .
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported in 14% of patients given bromocriptine for treatment of acromegaly during clinical trials (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    2) WITH POISONING/EXPOSURE
    a) Constipation has been reported as an overdose effect of bromocriptine (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    C) ABDOMINAL CRAMPS
    1) WITH THERAPEUTIC USE
    a) Abdominal cramps were reported in 4% of patients who received bromocriptine for treatment of hyperprolactinemic indications during clinical trials (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 82-year-old man with Parkinson's disease developed elevated liver enzyme concentrations approximately 4 days after beginning bromocriptine therapy, 5 mg twice daily, to treat levodopa-induced dyskinesias. The liver enzymes gradually decreased following discontinuation of the bromocriptine, but recurred approximately 5 days after restarting bromocriptine therapy. Cessation of bromocriptine therapy resulted in gradual normalization of the patient's liver enzyme concentrations (Liberato et al, 1992).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) RESPIRATORY ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/LISURIDE: A 21-month-old child developed respiratory acidosis (pH 7.32, pCO2 48 mmHg, pO2 86 mmHg, and HCO3 24 mEq/L), tachycardia (96 bpm), tachypnea (22 breaths per minute), a reduced level of consciousness (Glasgow Coma Scale score of 8), and persistent hypotension (76/52 mmHg) after inadvertent ingestion of 1 mg lisuride maleate tablets (approximately 0.075 mg/kg). With symptomatic and supportive therapy, including vasopressor administration, the patient completely recovered and was discharged approximately 4 days post-ingestion (Alahmadi & Mujawar, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis has been reported as an overdose effect of bromocriptine (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Bromocriptine mesylate is classified as FDA pregnancy category B. Congenital abnormalities have occurred following maternal bromocriptine therapy, but the incidences of malformation and spontaneous abortion are not considered greater than that reported for spontaneous occurrences in the population at large. Bromocriptine inhibits lactation and stroke has been reported in nursing mothers during postmarketing use of the drug. Therefore, bromocriptine is contraindicated for use in nursing mothers.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) There was no evidence of bromocriptine-induced birth defects in an analysis of data collected from 1276 pregnancies in women treated with bromocriptine at a mean daily dose of 5.8 mg (range, 1 to 40 mg). Although bromocriptine was discontinued within the first 8 weeks of pregnancy (mean of 29 days) in the majority of patients, eight patients were treated with the drug throughout pregnancy. Of these 1276 pregnancies, there were 1088 full-term deliveries, 4 stillbirths, 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Twelve extrauterine gravidities and 3 hydatidiform moles, with 2 occurring in the same patient, resulted in early termination of pregnancy. These data are comparable to the abortion rate of 11 to 25% reported for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. The estimated frequency of spontaneous abortions in the general population is 10 to 15%. Birth defects occur in the general population at a frequency of 2 to 4.5%. The incidence of birth defects in 1109 live births from patients treated with bromocriptine was 3.3%. These data suggest that bromocriptine did not contribute to the type or incidence of birth defects in this analysis (Prod Info CYCLOSET oral tablets, 2009).
    2) There was no suggestion of any adverse effects on postnatal development resulting from intrauterine exposure to bromocriptine in a review of 4 different multicenter surveillance programs that analyzed 2351 pregnancies of 2185 women treated with bromocriptine and followed 583 of the children for a minimum of 3 to 12 months. Most of the women (75% or greater) had been treated with bromocriptine at doses of 5 to 10 mg/day for 2 to 8 weeks. There was 1 spontaneous abortion out of 93 pregnancies among 86 women treated with bromocriptine mostly for prolactinoma throughout pregnancy or from week 30 through the remainder of the pregnancy. Similar results have been shown in a Japanese hospital survey of 442 children born to 434 patients treated with bromocriptine during pregnancy and followed for at least one year (Prod Info CYCLOSET oral tablets, 2009).
    3) The use of bromocriptine during pregnancy was not associated with congenital malformations in a study of 2587 pregnancies (Krupp & Monka, 1987).
    4) In a study of the effects of mothers treated with bromocriptine before and during pregnancy, none of the teratogenic or mutagenic effects on the offspring were attributable to bromocriptine (Czeizel et al, 1989).
    B) ANIMAL STUDIES
    1) MONKEYS, RATS - There was no evidence of teratogenic effects in rats or monkeys following bromocriptine exposure that was up to 72 times and 10 times the human daily dose, respectively (Prod Info CYCLOSET oral tablets, 2009).
    2) RABBITS - In two strains of pregnant rabbits treated from gestation day 6 through 18 with oral doses up to 1400 times the human dose, low incidences of fetal abnormalities were observed at 480 to 1400 times the human dose. There were no treatment-related fetal abnormalities at doses 140 times the human dose (Prod Info CYCLOSET oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Bromocriptine is classified by the manufacturer as FDA pregnancy category B (Prod Info CYCLOSET oral tablets, 2009)
    B) LACK OF EFFECT
    1) In a study of 1335 women, use of bromocriptine did not increase the risk of fetal effects, abortion, multiple pregnancy, or congenital malformations (Turkalj et al, 1982; Krupp, 1985).
    2) The use of bromocriptine during pregnancy was not associated with spontaneous abortion in a study of 2587 pregnancies (Krupp & Monka, 1987).
    C) ANIMAL STUDIES
    1) RATS - When male rats given oral bromocriptine doses up to 120 times the human dose were mated with untreated females, there was a slight increase in pup loss at 24 to 120 times the human dose (Prod Info CYCLOSET oral tablets, 2009).
    2) RABBITS - In two strains of pregnant rabbits treated from gestation day 6 through 18 with oral doses up to 1400 times the human dose, there was maternal toxicity and embryolethality at doses 48 times the human dose. Implantation was not affected in rabbits treated from gestation day 1 through 6 with oral doses 480 to 1400 times the human dose (Prod Info CYCLOSET oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Bromocriptine is contraindicated for use in nursing mothers due to the inhibition of lactation and the incidence of stroke reported in this patient population. Possible hazards, including death, have been associated with the use of bromocriptine for lactation suppression. The reported events included 31 women who had strokes, nine of whom died, and 63 women who had seizures. Of the women with strokes or seizures, no other cause for the adverse events could be determined in 40% the cases. The absolute incidence as well as the relative risk of adverse events have not been clearly defined. Therefore, bromocriptine is no longer indicated for the prevention of physiological lactation (Rayburn, 1996).
    B) LACK OF EFFECT
    1) A woman successfully breast-fed her second child while on bromocriptine for diagnosed hyperprolactinemia, with the help of intensive counseling sessions and family support. The child began breast-feeding on the third day postpartum, regained birth weight (3.2 kilograms) on day 10 and was discharged. On follow-up, the infant weighed 6 kilograms at 5 months of age (Verma et al, 2006).
    2) Six women with macroadenomas and two women with microadenomas took bromocriptine throughout their pregnancies and during puerperium. All eight infants were born without anomalies. One of these women continued to successfully breast-feed while taking bromocriptine, 5 mg/day for a pituitary tumor. No adverse effects occurred in the infant (Canales et al, 1981).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS - There was no effect on fertility when female rats and male rats were treated with oral doses 2 to 7 times and up to 120 times the human 4.8-mg daily dose, respectively. In female rats, bromocriptine exposure occurred from 2 weeks prior to mating through 2 weeks post-mating or throughout lactation. Postnatal pup weight gain was reduced dose-dependently in treated groups probably due to lactation inhibition (Prod Info CYCLOSET oral tablets, 2009).

Genotoxicity

    A) No teratogenic or mutagenic effects can be attributed to bromocriptine treatment either before or during pregnancy.
    1) Czeizel et al (1989) studied the effects of mothers treated with bromocriptine before and during pregnancy and was unable to attribute any teratogenic or mutagenic effects on the offspring to bromocriptine.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure and ECG in symptomatic patients. Monitor for CNS signs of dyskinesias or seizures.
    B) Monitor serum electrolytes and acid/base balance in patients with prolonged vomiting or seizures.
    C) Bromocriptine plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Monitor serum electrolytes and acid/base balance in patients with prolonged vomiting or seizures.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor CNS changes for possible dyskinesias or seizures.
    b) Monitor blood pressure and ECG in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) Urine analysis by GC/MS revealed a bromocriptine-like substance at a base peak of 154 m/z, that was subsequently determined to be ergocalciferol from an infant formula (Cheng et al, 1987).

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 who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, who remains asymptomatic, can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor blood pressure and ECG in symptomatic patients. Monitor for CNS signs of dyskinesias or seizures.
    B) Monitor serum electrolytes and acid/base balance in patients with prolonged vomiting or seizures.
    C) Bromocriptine plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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) SUPPORT
    1) At present, the dangers of overdose with bromocriptine appear minimal and treatable with supportive care (Warren & Nakfoor, 1983; Vermund et al, 1984).
    2) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Manage mild hypotension with IV fluids. Control agitation and confusion with benzodiazepines. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    3) MANAGEMENT OF SEVERE TOXICITY
    a) Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure and ECG in symptomatic patients. Monitor for CNS signs of dyskinesias or seizures.
    2) Monitor serum electrolytes and acid/base balance in patients with prolonged vomiting or seizures.
    3) Bromocriptine plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) 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) Due to the high protein binding of bromocriptine (90% to 96%), hemodialysis is unlikely to be of benefit (Prod Info Parlodel(R) oral tablets, oral capsules, 2012; Prod Info CYCLOSET(R) oral tablets, 2010).

Abstracts

Case Reports

    A) PEDIATRIC
    1) Ingestion of 7.5 mg bromocriptine in a 2.5-year-old boy resulted in vomiting and lethargy within 2 hours. Progressive somnolence and mydriasis occurred followed by complete recovery within 24 hours (Vermund et al, 1984).
    2) A 2-year-old boy ingested 25 mg of bromocriptine, vomited, and was lethargic within 1.5 hours. Systolic blood pressure was 60 by palpation, breathing was shallow, pupils dilated, and lower extremities were hyperreflexic.
    a) Within 30 minutes breathing had returned to normal and blood pressure increased. Full recovery occurred (Vermund et al, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Bromocriptine overdoses up to 25 mg in children have resulted in vomiting and drowsiness. A lisuride ingestion of 1 mg in a toddler resulted in respiratory acidosis and persistent hypotension. The child recovered with symptomatic and supportive care.
    B) THERAPEUTIC USE: Varies by disease state in adults. ACROMEGALY: Bromocriptine: Usual dosage range of 20 to 30 mg daily; maximum dose of 100 mg daily. DIABETES MELLITUS TYPE 2: Bromocriptine: Usual dosage range is 1.6 to 4.8 mg once daily; maximum daily dose is 4.8 mg. HYPERPROLACTINEMIA: Bromocriptine: Usual dosage range of 2.5 to 15 mg daily. PARKINSON'S DISEASE: Bromocriptine: Initial dose is 1.25 mg twice daily, increasing by 2.5 mg daily every 14 to 28 days as needed; maximum dose of 100 mg/day. CHILDREN (11 to 15 years): For prolactinoma, the bromocriptine maintenance dosage regimen is 2.5 to 10 mg daily, based on limited data from clinical trials.

Therapeutic Dose

    7.2.1) ADULT
    A) BROMOCRIPTINE
    1) SPECIFIC DISEASE STATE
    a) ACROMEGALY: Initially, the recommended dose is 1.25 to 2.5 mg orally at bedtime for 3 days. The dose may be increased by 1.25 to 2.5 mg every 3 to 7 days as needed. The usual maintenance dosage regimen is 20 to 30 mg daily. The maximum dose is 100 mg/day (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) DIABETES MELLITUS TYPE 2: Initially, 0.8 mg orally once daily. The dose may be increased by 0.8 mg weekly. The usual dosage range is 1.6 to 4.8 mg once daily. The maximum daily dose is 4.8 mg. The dose should be taken within 2 hours after waking in the morning (Prod Info CYCLOSET(R) oral tablets, 2010).
    c) HYPERPROLACTINEMIA: 1.25 to 2.5 mg orally once daily. The dose may be increased by 2.5 mg every 2 to 7 days as needed. The usual dosage range is 2.5 to 15 mg daily (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    d) PARKINSON'S DISEASE: Initially, the recommended dose is 1.25 mg orally twice daily. The dosage may be increased by 2.5 mg daily every 14 to 28 days as needed. The maximum dose is 100 mg/day (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    7.2.2) PEDIATRIC
    A) BROMOCRIPTINE
    1) SPECIFIC DISEASE STATE
    a) PROLACTINOMA (11 to 15 years of age): Based on limited data from clinical trials, the initial recommended dose is 1.25 to 2.5 mg orally daily. The maintenance dosage regimen is 2.5 to 10 mg daily (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).
    b) Safety and efficacy have not been established in pediatric patients for any other FDA approved indication (Prod Info Parlodel(R) oral tablets, oral capsules, 2012).

Maximum Tolerated Exposure

    A) BROMOCRIPTINE
    1) PEDIATRIC
    a) Hypotension and tachycardia were reported in one 2-year-old child (of 18 cases) (Vermund et al, 1984).
    b) Ingestion of as little as 7.5 mg (3 tablets) in two young children resulted in lethargy (Vermund et al, 1984).
    c) A 2-year-old child who ingested 25 mg developed vomiting, drowsiness, hypotension, mydriasis and hyperreflexia, but had a complete recovery (Vermund et al, 1984).
    B) LISURIDE
    1) PEDIATRIC
    a) CASE REPORT: A 21-month-old child developed respiratory acidosis (pH 7.32, pCO2 48 mmHg, pO2 86 mmHg, and HCO3 24 mEq/L), tachycardia (96 bpm), tachypnea (22 breaths per minute), a reduced level of consciousness (Glasgow Coma Scale score of 8), and persistent hypotension (BP 76/52 mmHg) after inadvertent ingestion of 1 mg lisuride maleate tablets (approximately 0.075 mg/kg). With symptomatic and supportive therapy, including vasopressor administration, the patient completely recovered and was discharged approximately 4 days postingestion (Alahmadi & Mujawar, 2013).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) BROMOCRIPTINE
    1) LD50- (ORAL)MOUSE:
    a) >800 mg/kg (RTECS, 2001)
    B) BROMOCRIPTINE MESYLATE
    1) LD50- (ORAL)MOUSE:
    a) 2502 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) >2 g/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bromocriptine is a synthetic ergoline and a direct dopamine D2 agonist stimulant. In addition, bromocriptine has a high affinity for 5-HT2A and 5-HT2B receptors. It also has properties as a D1-receptor antagonist (Kvernmo et al, 2006).
    B) Some of bromocriptine's activity includes inhibition of the release of prolactin by the pituitary, resulting in decreased plasma prolactin concentrations. Bromocriptine, as a dopamine agonist, occupy dopaminergic receptors in the pituitary gland to inhibit prolactin secretion (Barbieri & Ryan, 1983).
    C) The D2 receptor sites showed properties related to dopaminergic behavioral and endocrine responses (Calne, 1980; Larsen & Calne, 1982; Kebabian et al, 1979). Reduced tonic stimulation of dopaminergic D-2 receptors located on intrastriatal cholinergic neurons are the most likely cause of the parkinsonian symptoms (Sethy, 1979; Scatton, 1982).
    D) It is suggested that bromocriptine, as a dopamine D2 receptor agonist, may augment dopamine levels in the hypothalamus and inhibit the excessive sympathetic tone within the CNS, thereby enhancing the suppression of hepatic glucose production and resulting in a decrease in post-prandial glucose levels (Shivaprasad & Kalra, 2011). In addition, bromocriptine may reverse the elevated fasting and post-prandial levels in insulin-resistant patients by acting on the circadian cycle in the hypothalamus and resetting an abnormally elevated hypothalamic drive that results in increased plasma glucose, triglyceride, and free fatty acid levels (Shivaprasad & Kalra, 2011; Keche, 2010).

Physicochemical

Physical Characteristics

    A) Bromocriptine mesylate is a white or slightly colored fine crystalline powder (Prod Info CYCLOSET oral tablets, 2009).

Molecular Weight

    A) 750.72 (Prod Info CYCLOSET oral tablets, 2009)

References

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