MOBILE VIEW  | 

MIRABEGRON

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Mirabegron is a beta-3 adrenergic agonist which increases bladder capacity by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle.

Specific Substances

    1) Mirabegronum
    2) YM-178
    3) CAS 223673-61-8
    1.2.1) MOLECULAR FORMULA
    1) C21-H24-N4-O2-S (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Available Forms Sources

    A) FORMS
    1) Mirabegron is available as 25 mg and 50 mg extended-release tablets (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    B) USES
    1) Mirabegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Laboratory Monitoring

    A) Monitor vital signs in symptomatic patients or after large ingestions.
    B) No specific laboratory tests are necessary unless otherwise clinically indicated.
    C) 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. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not necessary.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENTS
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic, or have persistent severe hypertension or tachycardia despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Tmax, oral: 3.5 hours. Bioavailability, oral: 29% to 35%. Protein binding: approximately 71%. Vd: 1670 L. Mirabegron is transported and metabolized via multiple pathways involving dealkylation, oxidation, direct glucuronidation, and amide hydrolysis. It is a substrate for CYP3A4 and CYP2D6 (limited role), butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT), and possibly alcohol dehydrogenase. Excretion: renal: 6% to 12.2% unchanged. Elimination half-life: 50 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension or tachycardia (eg, sympathomimetic agents).

Range Of Toxicity

    A) TOXICITY: After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days.
    B) THERAPEUTIC DOSES: ADULTS: 25 to 50 mg orally once daily. CHILDREN: Safety and efficacy of mirabegron have not been established in pediatric patients.

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Mirabegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
    B) PHARMACOLOGY: Mirabegron is a beta-3 adrenergic agonist which increases bladder capacity by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Mirabegron is generally well-tolerated. GREATER THAN 2% AND GREATER THAN PLACEBO: Hypertension (up to 11.3%), urinary tract infections (up to 5.9%), nasopharyngitis (up to 3.9%), headache (up to 3.2%). RARE EFFECTS: Tachycardia, palpitations, pruritus, rash, urticaria, or leukocytoclastic vasculitis, abdominal distention, gastritis, dyspepsia, abdominal pain, diarrhea, constipation, bladder pain, nephrolithiasis, sinusitis, rhinitis, elevated liver enzymes.
    E) WITH POISONING/EXPOSURE
    1) After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days.
    0.2.20) REPRODUCTIVE
    A) Mirabegron is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of mirabegron use in pregnant women. Based on animal data, mirabegron is predicted to have a low probability of increased risk for adverse developmental outcomes when compared with background risk.
    0.2.21) CARCINOGENICITY
    A) Although neoplasm developed in clinical trials, a causal relationship was not established.

Summary Of Exposure

    A) USES: Mirabegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
    B) PHARMACOLOGY: Mirabegron is a beta-3 adrenergic agonist which increases bladder capacity by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Mirabegron is generally well-tolerated. GREATER THAN 2% AND GREATER THAN PLACEBO: Hypertension (up to 11.3%), urinary tract infections (up to 5.9%), nasopharyngitis (up to 3.9%), headache (up to 3.2%). RARE EFFECTS: Tachycardia, palpitations, pruritus, rash, urticaria, or leukocytoclastic vasculitis, abdominal distention, gastritis, dyspepsia, abdominal pain, diarrhea, constipation, bladder pain, nephrolithiasis, sinusitis, rhinitis, elevated liver enzymes.
    E) WITH POISONING/EXPOSURE
    1) After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) GLAUCOMA: Glaucoma occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension occurred during clinical trials with mirabegron in patients with overactive bladder. The mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 mmHg to 1 mmHg greater than placebo, but worsening of preexisting hypertension was infrequent (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    1) Hypertension occurred in 11.3% of adult patients with overactive bladder who received mirabegron 25 mg once daily (n=432), 7.5% of patients who received mirabegron 50 mg once daily (n=1375), and 7.6% of patients on placebo (n=1380) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    2) Hypertension occurred in 9.2% of adult patients with overactive bladder who received mirabegron 50 mg once daily (n=812) compared with 9.6% of patients on an active control (n=812; control not stated) in a 1-year, randomized, active-controlled safety trial (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Increases in systolic blood pressure developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    B) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia occurred in 1.6% of adult patients with overactive bladder who received mirabegron 25 mg once daily (n=432), 1.2% of patients who received mirabegron 50 mg once daily (n=1375), and 0.6% of patients on placebo (n=1380) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 4.1% of adult patients with overactive bladder who received mirabegron 50 mg once daily (n=812) compared with 2.5% of patients on an active control (n=812; control not stated) in a 1-year, randomized, active-controlled safety trial (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Abdominal distention, gastritis, or dyspepsia developed in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials. Abdominal pain (1.4%), diarrhea (1.2%), and constipation (1.6% to 2.8%) were also reported (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increases in ALT and AST levels occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infections occurred in 4.2% of adult patients with overactive bladder who received mirabegron 25 mg once daily (n=432), 2.9% of patients who received mirabegron 50 mg once daily (n=1375), and 1.8% of patients on placebo (n=1380) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    B) BLADDER PAIN
    1) WITH THERAPEUTIC USE
    a) Bladder pain occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    C) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Nephrolithiasis occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Pruritus, rash, urticaria, or leukocytoclastic vasculitis developed in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Mirabegron is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of mirabegron use in pregnant women. Based on animal data, mirabegron is predicted to have a low probability of increased risk for adverse developmental outcomes when compared with background risk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Animal data indicated reversible developmental findings of delayed ossification and wavy ribs in rats, and decreased fetal body weights in rabbits at exposures that were greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD) of 50 mg based on AUC. The pregnant rats received oral mirabegron up to 300 mg/kg/day from implantation to closure of the fetal hard palate (7th to 17th day of gestation). The pregnant rabbits received oral mirabegron up to 30 mg/kg/day from implantation to closure of the fetal hard palate (6th to 20th day of gestation). At maternally toxic exposures, decreased fetal weights were noted in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Mirabegron is classified as FDA pregnancy category C (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    2) There are no adequate and well-controlled studies of mirabegron use in pregnant women. Mirabegron should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether mirabegron is excreted in human breast milk, and no studies have been conducted to assess the impact of mirabegron on milk production or the potential effects on a nursing infant. Since human breast milk excretion may occur and adverse effects are possible in a nursing infant, the manufacturer recommends either discontinuation of nursing or mirabegron therapy based on the potential benefit to the mother (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    B) ANIMAL STUDIES
    1) In animal studies, mirabegron was measured in rat milk at concentrations that were twice the maternal plasma level, and nursing pups had mirabegron in the lungs, liver, and kidneys (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, no adverse fertility effects were observed in either male or female rats after exposures to non-lethal doses up to 100 mg/kg/day (about 22 times the MRHD in women and 93 times the MRHD in men) (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Nasopharyngitis occurred in 3.5% of adult patients with overactive bladder who received mirabegron 25 mg once daily (n=432), 3.9% of patients who received mirabegron 50 mg once daily (n=1375), and 2.5% of patients on placebo (n=1380) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    b) Nasopharyngitis occurred in 3.9% of adult patients with overactive bladder who received mirabegron 50 mg once daily (n=812) compared with 3.1% of patients on an active control (n=812; control not stated) in a 1-year, randomized, active-controlled safety trial (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    B) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) Sinusitis occurred in 2.7% of adult patients with overactive bladder who received mirabegron 50 mg once daily (n=812) compared with 1.5% of patients on an active control (n=812; control not stated) in a 1-year, randomized, active-controlled safety trial (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).
    C) RHINITIS
    1) WITH THERAPEUTIC USE
    a) Rhinitis distention occurred in less than 1% of adult patients with overactive bladder who received either mirabegron 25 mg, 50 mg, or 100 mg once daily (n=2736) in three, 12-week, randomized, placebo-controlled trials (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Although neoplasm developed in clinical trials, a causal relationship was not established.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) Neoplasm occurred in 0.1%, 1.3%, and 0.5% of adult patients with overactive bladder who received mirabegron 50 mg once daily (n=812), mirabegron 100 mg once daily (n=820), or an active control (n=812; control not stated), respectively, in a 1-year, randomized, active-controlled safety trial. Breast cancer, malignant lung cancer, and prostate cancer were reported in 2 patients who received mirabegron 100 mg (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012). A causal relationship was established.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) MICE AND RATS: In long-term (2 years) animal carcinogenicity studies, mirabegron was not carcinogenic following systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure to mirabegron 50 mg (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Genotoxicity

    A) In studies, there was no evidence of mutagenicity of mirabegron in Ames bacterial reverse mutation assay. In addition, there was no evidence of clastogenicity in the rat micronucleus assay and mirabegron did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in symptomatic patients or after large ingestions.
    B) No specific laboratory tests are necessary unless otherwise clinically indicated.
    C) Plasma concentrations are not readily available or clinically useful in the management of overdose.

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, or have persistent severe hypertension or tachycardia despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that 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 in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs in symptomatic patients or after large ingestions.
    B) No specific laboratory tests are necessary unless otherwise clinically indicated.
    C) 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 necessary.
    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 in symptomatic patients and those with large overdose.
    2) No specific laboratory tests are necessary unless otherwise clinically indicated.
    3) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    16) LABETALOL
    a) INTRAVENOUS INDICATIONS
    1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.
    b) ADULT DOSE
    1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
    2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).
    c) PEDIATRIC DOSE
    1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).
    d) ADVERSE REACTIONS
    1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).
    e) PRECAUTIONS
    1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
    2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).
    f) MONITORING PARAMETER
    1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the large volume of distribution.

Summary

    A) TOXICITY: After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days.
    B) THERAPEUTIC DOSES: ADULTS: 25 to 50 mg orally once daily. CHILDREN: Safety and efficacy of mirabegron have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial, 25 mg orally once daily, may increase to 50 mg orally once daily after 8 weeks based on efficacy and tolerability (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012)
    7.2.2) PEDIATRIC
    A) Safety and efficacy of mirabegron have not been established in pediatric patients (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Maximum Tolerated Exposure

    A) After receiving single doses up to 400 mg of mirabegron, palpitations and tachycardia (heart rate greater than 100 beats/min) developed in 1 and 3 healthy volunteers (n=6), respectively. Increases in pulse rate and systolic blood pressure also developed after volunteers received multiple doses of mirabegron up to 300 mg daily for 10 days (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Pharmacologic Mechanism

    A) Mirabegron is a beta-3 adrenergic agonist which increases bladder capacity by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012).

Physical Characteristics

    A) Practically insoluble in water (0.082 mg/mL); soluble in methanol and dimethyl sulfoxide (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012)

Molecular Weight

    A) 396.51 (Prod Info MYRBETRIQ(TM) oral extended-release tablets, 2012)

General Bibliography

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    2) Bunchman TE, Lynch RE, & Wood EG: Intravenously administered labetalol for treatment of hypertension in children. J Pediatr 1992; 120(1):140-144.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Deal JE , Barratt TM , & Dillon MJ : Management of hypertensive emergencies. Arch Dis Child 1992; 67(9):1089-1092.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Fivush B , Neu A , & Furth S : Acute hypertensive crises in children: emergencies and urgencies. Curr Opin Pediatr 1997; 9(3):233-236.
    8) Flynn JT & Tullus K: Severe hypertension in children and adolescents: pathophysiology and treatment. Pediatr Nephrol 2009; 24(6):1101-1112.
    9) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
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    13) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    14) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    15) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    16) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    17) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    18) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    19) Miller K: Pharmacological management of hypertension in paediatric patients. A comprehensive review of the efficacy, safety and dosage guidelines of the available agents. Drugs 1994; 48(6):868-887.
    20) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    21) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    22) Pearce CJ & Wallin JD: Labetalol and other agents that block both alpha- and beta-adrenergic receptors. Cleve Clin J Med 1994; 61(1):59-69.
    23) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    24) Product Information: MYRBETRIQ(TM) oral extended-release tablets, mirabegron oral extended-release tablets. Astellas Pharma US, Inc. (per FDA), Northbrook, IL, 2012.
    25) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    26) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    27) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    28) Product Information: Trandate(R) IV injection, labetalol hydrochloride IV injection. Prometheus Laboratories Inc., San Diego, CA, 2010.
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    32) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
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    34) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.