INDERAL LA (Brand for PROPRANOLOL HCL ER)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Immediate-release tablets: Administer with food.

-Sustained-release capsules (e.g., Inderal LA): Administer once daily. Do not crush or chew; swallow whole. If patients are switched from immediate-release tablets to sustained-release capsules, assure desired therapeutic effects are maintained. Substitution should not be simply considered 1:1 as lower plasma concentrations are achieved with the long-acting product. Further titration may be necessary.
-Extended-release capsules (e.g., Innopran XL): Administer once daily at bedtime. Do not crush or chew; swallow whole. Take consistently either on an empty stomach or with food.

Oral Liquid Formulations
-Neonates, infants, and small children receiving propranolol should be fed shortly after or concurrently with each dose to avoid hypoglycemic effects. Regular, frequent food intake is also recommended (e.g., feeds every 3-4 hours in infants < 6 weeks, every 5 hours for infants between 6 weeks and 4 months, and every 6-8 hours for infants > 4 months). Avoid fasting; if inevitable, hold the medication or support nutrition with a product such as Pedialyte or glucose-containing IV fluids. For patients being treated for infantile hemangiomas, it is recommended to skip the dose if the patient is not eating or is vomiting.
-Monitor blood pressure and heart rate.-For patients being treated for infantile hemangiomas, monitor blood pressure and heart rate 1 and 2 hours after the initial dose and after any significant dose increase (e.g., > 0.5 mg/kg/day). Clinical guidelines recommend obtaining vital signs and cardio-respiratory exam or ECG at baseline.


Hemangeol Oral Solution (4.28 mg/ml; for infantile hemangioma)
-Record the date on the box when the bottle is first opened.
-Do not shake the bottle before use.
-Administer during or right after a feeding.
-Using an oral syringe, administer the medicine directly into the child's mouth, against the inside of the cheek. If this is not feasible, the solution may be diluted in a small quantity of milk or fruit juice and given immediately.
-Keep the child in an upright position for a few minutes after giving the dose.
-Storage: Store the bottle in the box at room temperature and discard 2 months after opening.

Generic Oral Solution (4 mg/ml or 8 mg/ml)
-Administer with food.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
IV Push
-No dilution necessary. If a dilution is necessary for accurate dose delivery, drug may be diluted in D5W, NS, or Lactated Ringers.
-Administer via slow IV push over 10 minutes. Do not exceed a rate of 1 mg/min.
-A second dose may be given after 2 minutes if an additional immediate dose is necessary (e.g., for tetralogy spells).
-Monitor ECG and central venous pressure during IV administration.

Oral propranolol appears to have a favorable safety profile in pediatric patients. Neonates and infants are more sensitive to the negative inotropic and chronotropic effects of propranolol and intravenous propranolol should be used with extreme caution. In addition, limited glycogen stores and higher glucose utilization rates in neonates, infants, and young children increase the risk of low blood glucose concentrations with propranolol use.

In clinical trials for proliferating infantile hemangioma (n = 479), the most frequently reported adverse reactions (more than 10%) in patients treated with propranolol oral solution (Hemangeol) were sleep disorders, gastrointestinal effects, and aggravated bronchitis or bronchiolitis with associated symptoms. Adverse reactions led to treatment discontinuation in less than 2% of treated patients. Of those evaluated, 424 patients were treated with doses at 1.2 mg/kg/day or 3.4 mg/kg/day for 3 or 6 months. The majority (63%) of patients were 91 to 150 days of age at randomization; the remaining 37% were aged 35 to 90 days. Other dosage forms of propranolol are not FDA-approved for pediatric use and, hence, safety profiles have not been formally evaluated.

Propranolol may cause or worsen sinus bradycardia (less than 1%) or hypotension. Although these adverse events are not common when the dosage is carefully titrated, they can be serious in certain patients. Both tend to be mild and asymptomatic in children treated for infantile hemangiomas who have no preexisting comorbidities. During clinical trials for infantile hemangioma, the mean decrease in heart rate was about 7 bpm with little effect on blood pressure. In patients being treated for infantile hemangioma, it is recommended to monitor heart rate and blood pressure for 2 hours after treatment initiation or any significant increase in dose. Discontinue treatment if severe (less than 80 bpm) or symptomatic bradycardia or hypotension (systolic blood pressure less than 50 mmHg) occurs. Hypotension and bradycardia in hospitalized patients can be reversed with atropine and intravenous fluids, if necessary. Bradycardia and hypotension can also occur with the use of any propranolol formulation for other indications.

AV block, secondary to depressed conduction at the AV node, may necessitate sympathomimetic and/or pressor therapy or use of a temporary pacemaker. During clinical trials for infantile hemangioma, second degree AV block, in a patient with an underlying conduction disorder, required definitive treatment discontinuation. Use of a beta-blocker may worsen pre-existing heart failure. Congestive heart failure has been reported with the use of propranolol in pediatric patients. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of propranolol therapy. Elevations of blood urea nitrogen also have been reported in patients with severe heart failure who are taking propranolol.

Arterial insufficiency, usually of the Raynaud type, and paresthesias of the hands have been reported with propranolol use. Peripheral coldness was reported in 7% to 8% of infants during infantile hemangioma clinical trials.

Propranolol can cause hypoglycemia; decreased blood glucose concentrations occurred in less than 1% of infants during infantile hemangioma clinical trials. Beta-blockers prolong or enhance hypoglycemia by interfering with catecholamine-induced glycogenolysis, gluconeogenesis, and lipolysis; this effect may be less pronounced with beta1-selective agents than with nonselective agents. Additionally, they can mask signs of hypoglycemia, including tachycardia, palpitations, tremors, and sweating. Young children and infants, especially those younger than 3 months of age, are at particular risk for this complication. Hypoglycemia is much more common in patients during periods of fasting (e.g., irregular feeding schedules, preoperative intake abstinence, vomiting), after prolonged physical exertion, or in those with renal disease or insufficiency. To reduce the risk of hypoglycemia, propranolol should be administered with feeds and the dose should be held if the child is not eating or is vomiting. The risk of hypoglycemia increased after 8 hours or more of fasting in infants and young children. Hypoglycemic symptoms are often difficult to detect in infants and children. Hypoglycemia may present in the form of seizures, lethargy, or coma. Careful monitoring (vital signs, blood glucose concentrations) during initiation and slow dose escalation are recommended. Clinicians should advise caregivers of appropriate measures to decrease the risk of hypoglycemia, focusing on the importance of frequent feedings (every 3 to 4 hours in infants, with nutrition given shortly before or after administration). In addition, caregivers should be provided with special instructions for dosage adjustment or discontinuation during intercurrent illness (if clinical condition allows) and alternative dietary recommendations. Inform caregivers to discontinue propranolol and seek immediate medical attention if clinical signs of hypoglycemia are present. Administration of dextrose-containing IV fluids may be necessary.

Diarrhea (4.5% to 6%), anorexia or decreased appetite (2.5% to 3.5%), abdominal pain (0.5% to 3.5%), and vomiting were among the most common adverse reactions associated with propranolol use in infants during infantile hemangioma clinical trials. Other gastrointestinal effects including nausea, constipation, abdominal cramping, epigastric distress, mesenteric arterial thrombosis, and ischemic colitis have been reported in adult patients taking propranolol.

Bronchospasm has been reported coincident with propranolol therapy in pediatric patients. Patients with preexisting bronchospastic disease are at high risk for exacerbation of asthma, dyspnea, or bronchospasm when treated with propranolol. During infantile hemangioma clinical trials, aggravated respiratory tract infection such as bronchitis (8% to 13%) and bronchiolitis associated with cough and fever were among the most frequently reported adverse events. In the event of a lower respiratory tract infection associated with dyspnea and wheezing, propranolol therapy should be interrupted if the clinical condition allows (e.g., treatment for hemangioma).

Unspecified sleep disorders (16% to 17.5%), nightmares, (2% to 6%), agitation (4.5% to 8.5%), irritability (1% to 5.5%), and drowsiness (0.9% to 5%) were among the most common adverse events associated with propranolol use in infants during infantile hemangioma clinical trials. Patients who experience sleep disturbances may require a lower propranolol dose. Other central nervous system effects including dizziness, lethargy, fatigue, weakness, catatonia, an acute reversible syndrome characterized by disorientation to time and place, visual impairment, hallucinations, short-term memory impairment, emotional lability, slightly clouded sensorium (e.g., confusion), vivid dreams, decreased performance on neuropsychometrics, and depression manifested by insomnia have been reported in adult patients taking propranolol. With immediate-release formulations, fatigue, lethargy, and vivid dreams appear to be dose-related. Symptoms such as lethargy and stupor may be a sign of hypoglycemia; if hypoglycemia is suspected, caregivers should discontinue propranolol and seek immediate medical attention.

Some beta-blockers, including propranolol, have been shown to cause hypertriglyceridemia and decrease plasma HDL levels during therapy in adult patients. The clinical implications of these effects, in light of other cardiovascular advantages of beta-blocker therapy, are not known.

Isolated reports of myopathy and myotonia exacerbation have been reported with the use of extended-release propranolol capsules. Use propranolol with caution in patients with preexisting skeletal muscle disease.

In adult hypertensive patients, propranolol has been associated with hyperkalemia and elevated hepatic enzymes (e.g., serum transaminases and alkaline phosphatase).

Rare but severe hematologic side effects, such as agranulocytosis, have been reported with propranolol therapy. Non-thrombocytopenic purpura and thrombotic thrombocytopenic purpura (TTP) also have been reported.

Dermatologic and hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis, erythematous rash, urticaria (less than 1%), fever combined with aching and sore throat, laryngospasm, and respiratory distress have been reported with propranolol use. In addition, Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme, and psoriasiform dermatitis have been associated with propranolol use. In general, dermatologic reactions, such as pruritus, alopecia (less than 1%), xerosis, xerophthalmia, and exfoliative dermatitis are mild and transient. Psoriaform rash is the most common cutaneous reaction of beta-blocker therapy. Drug-induced/aggravated psoriasis typically appears 1 to 18 months after therapy initiation. For localized eruptions, emollient application may be helpful. Discontinuation of the beta-blocker can cause rapid disease regression and lesions may clear within several weeks. Re-exposure often results in recurrence.

Lupus-like symptoms and systemic lupus erythematosus have been reported rarely with the use of propranolol.

Withdrawal symptoms, including headache, diaphoresis, palpitations, sinus tachycardia, tremor, and hypertension, have been associated with abrupt discontinuation of beta-blockers in hypertensive patients. Gradual tapering and/or prolonged administration of small doses of propranolol prior to complete cessation may prevent these symptoms.

Occasionally, beta-blockers cause hyperglycemia in the general population; this is thought to be due to blockade of beta2-receptors on pancreatic islet cells, which would inhibit insulin secretion. Hyperglycemia was not reported in clinical trials of infants receiving propranolol for the treatment of hemangioma. In addition to acute blood glucose effects, beta-blockers have been shown to increase the risk of developing diabetes mellitus in adult hypertensive patients. The risk in pediatric patients is undefined.

Male impotence (erectile dysfunction) has been reported with various beta-blocker therapies, including propranolol. Peyronie's disease (an abnormal curvature of the penis during erection with penile fibrosis) has also been reported with propranolol, but is considered to be very rare.

Abrupt discontinuation of propranolol can result in the exacerbation of angina and, in some cases, myocardial infarction. If chronic, oral propranolol therapy is to be discontinued, gradually decrease the dosage over a minimum of 2 weeks. Downward titration of parenteral therapy may be advisable if the patient will discontinue propranolol treatment. Advise patients and caregivers against interruption or cessation of therapy without the advice of a physician. If exacerbation of angina occurs during discontinuation of therapy, it is advised to reinstitute propranolol therapy and take other measures appropriate for the management of unstable angina.

Beta-blockers, like propranolol, should be used with caution in patients with hyperthyroidism or thyrotoxicosis because beta-blockade may mask clinical signs of hyperthyroidism, including tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. It should be noted that propranolol is often used for the acute symptomatic treatment of the thyrotoxic patient. Beta-blockers can reduce tachycardia, tremor, and anxiety in the hyperthyroid patient.

Propranolol oral solution for infantile hemangiomas (Hemangeol) is contraindicated in premature neonates, neonates, and infants with a corrected age younger than 5 weeks as well as any infant weighing less than 2 kg. Clinical guidelines recommend caution, but not exclusion, in infants younger than 5 weeks of age and/or postconceptual age younger than 48 weeks. Propranolol therapy can cause hypoglycemia, particularly in neonates, infants, and children. Propranolol-induced hypoglycemia may be more common during periods of fasting (e.g., irregular feeding schedules, preoperative intake abstinence, vomiting), after prolonged physical exertion, in patients with renal insufficiency, or when glucose demands are increased (e.g., cold, stress, infections). Neonates and infants younger than 3 months of age are at higher risk for drug-induced hypoglycemia; in patients receiving propranolol for hemangioma, doses should be held during periods of irregular feeding or vomiting. Beta-blockers prolong or enhance hypoglycemia by interfering with catecholamine-induced glycogenolysis, glyconeogenesis, and lipolysis. Additionally, they can mask signs of hypoglycemia, including tachycardia, palpitations, tremors, and diaphoresis. Hypoglycemic symptoms are often difficult to detect in infants and young children. Careful monitoring (vital signs, blood glucose concentrations) during initiation and slow dose escalation are recommended. Advise caregivers of appropriate measures to decrease the risk of hypoglycemia, focusing on the importance of frequent feedings (every 3 to 4 hours, with nutrition given shortly before or after administration). In addition, provide caregivers with special instructions for dosage adjustment or discontinuation during intercurrent illness (if clinical condition allows) and alternative dietary recommendations. Inform caregivers to discontinue propranolol and seek immediate medical attention if signs of hypoglycemia are present. Administration of dextrose-containing IV fluids may be necessary. In addition to acute blood glucose effects, beta-blockers have been shown to increase the risk of developing diabetes mellitus in adult hypertensive patients. The risk in pediatric patients receiving chronic propranolol therapy is not known. Use propranolol with caution in young patients and those with poorly controlled or brittle diabetes mellitus.

Propranolol is contraindicated in patients with sinus bradycardia and second or third degree AV block, unless a functioning pacemaker is present, because it depresses conduction through the AV node. Reduction in heart rate and cardiac output may cause or worsen bradycardia and hypotension. Propranolol oral solution for infantile hemangioma (Hemangeol) is specifically contraindicated in infants with significant bradycardia or hypotension defined as a heart rate less than 80 beats per minute or blood pressure less than 50/30 mmHg. Clinical guidelines state that evidence of cardiogenic shock or heart failure, sinus bradycardia, or heart block greater than first degree are potential exclusions for the use of propranolol for infantile hemangioma that require appropriate subspecialty evaluation and clearance. Propranolol is also contraindicated in patients with sick sinus syndrome unless a functioning pacemaker is present. In general, beta-blockers should not be used in patients with acute pulmonary edema and are contraindicated in patients with cardiogenic shock or decompensated acute heart failure, particularly in those with left ventricular dysfunction, because the negative inotropic effect of these drugs can further depress cardiac output. Of note, continued use of beta-blockers in patients without a history of heart failure can, in some cases, lead to cardiac failure. Neonates and infants are more sensitive to the negative inotropic and chronotropic effects of propranolol, and intravenous propranolol should be used with extreme caution in these populations. Monitor heart rate and blood pressure closely after treatment initiation or dose escalation with any dosage form; in patients being treated for infantile hemangiomas, heart rate and blood pressure should be closely monitored for 2 hours after initiation and any significant dose escalation. Discontinue treatment if severe (less than 80 bpm) or symptomatic bradycardia or hypotension (less than 50 mmHg systolic blood pressure) occurs.

Propranolol oral solution for infantile hemangioma (Hemangeol) is contraindicated in patients with pheochromocytoma. In general, beta-blocker monotherapy should be used with caution in patients with a pheochromocytoma or vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed alpha-receptor stimulation. In patients with pheochromocytoma, an alpha-blocking agent should be used prior to the initiation of any beta-blocker.

Beta-blockade with propranolol in patients with Wolff-Parkinson-White syndrome and tachycardia can result in severe bradycardia requiring treatment with a pacemaker.

Because of potential effects of beta-blockade on blood pressure and pulse, beta-blockers, particularly nonselective agents like propranolol, should be used with caution in patients with cerebrovascular disease or those at risk for stroke. If signs or symptoms suggesting reduced cerebral blood flow develop after beta-blocker initiation, consider alternative therapy. Propranolol therapy may increase the risk of stroke in patients with PHACE syndrome (Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/aortic coarctation, and abnormalities of the Eye), particularly those with severe cerebrovascular anomalies. PHACE syndrome is a potential exclusion for the use of propranolol for infantile hemangioma that requires appropriate subspecialty evaluation and clearance. Prior to initiation of propranolol therapy, investigate infants with large facial hemangiomas for potential arteriopathy associated with PHACE syndrome. Perform a MRI and/or MRA of the head and neck and echocardiography before or shortly after treatment initiation. Use the lowest effective dose, titrate slowly, and administer the daily dose divided 3 times daily to minimize abrupt changes in blood pressure. Comanagement with a pediatric neurologist is recommended.

Use propranolol with caution in patients with hepatic disease. Because of possible decreased drug clearance, reduced doses may be indicated. Propranolol is extensively metabolized by the liver.

Propranolol is contraindicated in patients with bronchial asthma or a history of bronchospasm. Clinical guidelines state that asthma and reactive airway disease are potential exclusions for the use of propranolol for infantile hemangioma that requires appropriate subspecialty evaluation and clearance. In general, propranolol should be avoided or used with great caution in patients with pulmonary disease, including acute bronchospasm, chronic lung disease (CLD), bronchitis, or pneumonia because of potential beta-adrenergic inhibition of bronchodilation. If the clinical condition allows, interrupt treatment in the event of a lower respiratory tract infection associated with dyspnea and wheezing.

Beta-blockers, like propranolol, may be associated with dizziness or drowsiness in some patients. Advise patients and their caregivers to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle) until the response is known.

Beta-blockers, like propranolol, may induce and/or exacerbate psoriasis.

Beta-blockers, like propranolol, may potentiate muscle weakness and diplopia in patients with myasthenia gravis.

The necessity or desirability of withdrawing beta-blockers, such as propranolol, prior to major surgery is controversial; the risks versus benefits should be evaluated in individual patients. Because beta-blocker therapy reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli, the risks of general anesthesia and surgical procedures may be augmented. Although gradual withdrawal of beta-blockers is sometimes recommended prior to general anesthesia to limit the potential for hypotension and heart failure, the manufacturer does not recommend withdrawal of chronically-administered propranolol prior to major surgery. The risk of precipitating adverse cardiac events (e.g., myocardial infarction, tachycardia) after preoperative withdrawal of beta-blockers may outweigh the risks of ongoing beta-blocker therapy, particularly in patients with coexisting cardiovascular disease. Monitor patients receiving beta-blockers before or during surgery involving the use of general anesthetics with negative inotropic effects (e.g., ether, cyclopropane, or trichloroethylene) closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in patients receiving beta-blockers. Consideration should be given to the type of surgery (e.g., cardiac vs. noncardiac), anesthetic strategy, and co-existing health conditions. The anesthetic technique may be modified to reduce the risk of concurrent beta-blocker therapy. If needed, the negative inotropic effects of beta-blockers may be cautiously reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg IV).

Tobacco smoking can increase the clearance rate of propranolol up to 77% to 100%, resulting in decreased plasma concentrations and possibly subtherapeutic clinical effects. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of propranolol (and potentially other beta-blockers), despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.

Use propranolol with caution in patients with underlying skeletal muscle disease. Isolated cases of exacerbation of myopathy and myotonia have been reported with use of the extended-release capsule.

Propranolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol. Do not use propranolol in patients with known beta-blocker hypersensitivity, as cross-sensitivity between beta-blockers may occur. In addition, patients receiving beta-blockers who have a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated allergen challenge and unresponsive to usual doses of epinephrine used to treat anaphylaxis.

Use propranolol with caution in patients with renal impairment because decreased plasma clearance may occur. In patients with renal failure, down-regulation of hepatic microsomal enzymes may result in decreased drug metabolism.

Avoid propranolol in patients with Raynaud's phenomenon or peripheral vascular disease because reduced cardiac output and the relative increase in alpha stimulation can exacerbate symptoms.

In utero exposure to propranolol, specifically administered during parturition, may result in neonatal bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available.

Description: Propranolol is the prototype of the beta-adrenergic receptor antagonists. It is a competitive, nonselective beta-blocker without intrinsic sympathomimetic activity, similar to nadolol. Propranolol is used in pediatric patients for the treatment or prevention of cardiac arrhythmias, hypertension, and tetralogy spells. In addition, propranolol can be used for migraine prophylaxis, symptom management in thyrotoxicosis, and infantile hemangiomas. Oral propranolol is the treatment of choice for problematic infantile hemangiomas that require systemic therapy; treatment is recommended in the presence of ulceration, vital function impairment (e.g., ocular compromise, airway obstruction), or risk of permanent disfigurement. Though generally well-tolerated when taken orally, beta-adrenergic effects (e.g., hypotension, bradycardia, hypoglycemia) can occur with propranolol use, and patients must be monitored appropriately. Neonates, infants, and young children are more sensitive to the negative inotropic and chronotropic effects of the drug (particularly when given intravenously) and are also at an increased risk for hypoglycemia due to lack of glycogen stores and higher glucose utilization rates. Caregivers should be given special instruction on the importance of frequent feedings, dosage adjustment or discontinuation (if clinical condition allows) during intercurrent illness, and alternative dietary recommendations. Hemangeol oral solution is the only propranolol product that is FDA-approved for pediatric use; it is indicated for patients as young as 5 weeks of age with infantile hemangiomas. Other formulations are not approved for pediatric use but are used clinically in patients as young as neonates.

For the treatment of a proliferating infantile hemangioma requiring systemic therapy:
To reduce the risk of hypoglycemia, administer propranolol immediately after or concurrently with a feeding. Avoid fasting; if inevitable, hold medication or support with a product such as Pedialyte or glucose-containing IV fluids. Vital signs and cardiorespiratory exam or ECG should be obtained at baseline. Obtain blood pressure and heart rate measurements at 1 and 2 hours after the initial dose and any significant dose increase (e.g., more than 0.5 mg/kg/day). Experts have recommended propranolol therapy continue until full involution of the lesion has occurred or the patient is at least 1 year of age; recurrences have been reported with early discontinuation. At the end of therapy, gradually taper propranolol over 2 to 4 weeks. If hemangiomas recur, treatment may reinitiated.
Oral dosage (FDA-approved dosage):
Infants 5 weeks to 5 months at initiation: 0.6 mg/kg/dose PO twice daily given at least 9 hours apart. After 1 week of treatment, increase dosage to 1.1 mg/kg/dose PO twice daily. After 2 weeks of treatment, increase dosage to 1.7 mg/kg/dose PO twice daily and maintain this dosage for 6 months. Readjust dosage periodically based on weight increases.
Oral dosage (alternative dosage recommended in clinical practice guidelines)*:
Neonates and Infants: 1 mg/kg/DAY PO initially, titrated to a target dose of 2 to 3 mg/kg/DAY, unless there are comorbidities (e.g., PHACE syndrome, progressive ulceration) or adverse reactions that require a lower dose. Administer in 2 to 3 divided doses; administer 3 times daily to minimize abrupt changes in blood pressure in high risk patients. Infantile hemangiomas often respond rapidly even to low doses of propranolol; dose escalation and optimal target dose should be based on individual patient response. Consensus guideline initiation protocols are based on corrected gestational age, social support status, and patient comorbidities affecting the cardiovascular or respiratory systems, and/or blood glucose maintenance. Inpatient initiation (neonates and infants younger than 8 weeks, inadequate social support, or comorbidities): 0.33 mg/kg/dose PO every 8 hours. If tolerated, increase dose to 0.66 mg/kg/dose PO every 8 hours and prepare for discharge. If the dose is not tolerated at any point in time, reduce the dosage and gradually increase to the target dose; it is recommended patients be discharged on a tolerated dose of at least 1 mg/kg/day. Outpatient initiation (infants older than 8 weeks and adequate social support): 0.33 mg/kg/dose PO given 3 times daily at least 6 hours apart. If tolerated for 3 to 7 days, increase dose to 0.5 mg/kg/dose PO given 3 times daily. If once again tolerated for 3 to 7 days, increase dose to 0.66 mg/kg/dose PO given 3 times daily. If the dose is not tolerated at any point in time, reduce the dosage and gradually increase to the target dose; consider a target dose of 1 mg/kg/day.

For the treatment of supraventricular tachycardia (SVT)*:
Intravenous dosage:
Neonates: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.
Infants: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.
Children and Adolescents: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 3 mg/dose, whichever is less.
Oral dosage (immediate-release):
Neonates: 0.5 to 1 mg/kg/day PO divided every 6 to 8 hours, initially. Increase the dose by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual dose: 2 to 4 mg/kg/day. Max: 16 mg/kg/day or 60 mg/day, whichever is less.
Infants, Children, and Adolescents: 0.5 to 1 mg/kg/day PO divided every 6 to 8 hours, initially. Increase the dose by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual dose: 2 to 4 mg/kg/day. Max: 16 mg/kg/day or 60 mg/day, whichever is less. In older adolescents, 10 to 30 mg/dose PO every 6 to 8 hours may be given.

For the prevention and treatment of hypercyanotic episodes associated with tetralogy of Fallot (i.e., tetralogy spells*):
Oral dosage (immediate-release):
Infants and Children: 1 mg/kg/day PO divided every 6 hours, initially. After 1 week, may titrate dose by 1 mg/kg/day every 24 hours as necessary. Average dose: 2.3 mg/kg/day (range: 0.8 to 5 mg/kg/day). Usual Max: 5 mg/kg/day. If the patient becomes refractory after initial control, may increase dose gradually to a maximum of 10 to 15 mg/kg/day; monitor heart size, heart rate, and cardiac contractility closely. Alternatively, 4 mg/kg/day PO divided every 6 hours has been used as an initial dose.
Intravenous dosage:
Infants and Children: 0.15 to 0.25 mg/kg/dose (Max: 1 mg/dose) IV; may repeat once. Alternatively, 0.01 to 0.02 mg/kg/dose IV has been used, reserving higher doses for refractory spells.

For the treatment of hypertension*:
Oral dosage (immediate-release formulations):
Neonates and Infants: 0.25 mg/kg/dose PO every 6 to 8 hours initially. Titrate gradually as needed for clinical effect; heart rate may be dose-limiting. Max: 3.5 mg/kg/dose; others recommend a max of 5 mg/kg/day.
Children and Adolescents: 0.5 to 2 mg/kg/day PO in 2 to 4 divided doses initially. Titrate gradually every 3 to 7 days as needed for clinical effect; heart rate may be dose-limiting. Usual effective dosage is 1 to 6 mg/kg/day. Max: 8 mg/kg/day or 640 mg/day, whichever is less. In adolescent patients, the sustained-release formulation may be given once daily.
Intravenous dosage:
Neonates: 0.01 mg/kg/dose slow IV push over 10 minutes, repeated every 6 to 8 hours as needed. Titrate gradually as needed for clinical effect; heart rate may be dose-limiting. Max: 0.15 mg/kg/dose.

For migraine prophylaxis*:
Oral dosage (immediate-release):
Children and Adolescents weighing 35 kg or less: 0.6 to 3 mg/kg/day PO given in 2 to 3 divided doses. Max: 60 mg/day. Pediatric patients receiving propranolol are possibly more likely than those receiving placebo to have at least a 50% reduction in headache frequency.
Children and Adolescents weighing more than 35 kg: 0.6 to 3 mg/kg/day PO given in 2 to 3 divided doses. Max: 120 mg/day. Pediatric patients receiving propranolol are possibly more likely than those receiving placebo to have at least a 50% reduction in headache frequency.

For the management of essential tremor*:
Oral dosage (immediate-release formulations):
Children: Limited experience; dosage often not reported in the literature; efficacy rate of 50%, along with side effect profile may lead to pursuit of other treatment options. 0.5 to 1 mg/kg/day PO, given in 3 divided doses has been recommended by some experts as an initial dose. Titrate dosage gradually once weekly as necessary; many patients respond to a dosage of 60 to 80 mg/day PO. Max: 4 mg/kg/day. Dosage may also be taken as needed 30 minutes prior to activities disrupted by essential tremor. Pharmacotherapy should be reserved for patients whose tremor is functionally or socially limiting; most do not require therapy until adolescence. Once an optimal dosage is determined, patients may transition to an extended-release formulation of propranolol, to be given once daily. Many patients require larger doses after 1 year of therapy, due to drug tolerance and disease progression.
Adolescents: Limited experience; dosage often not reported in the literature; efficacy rate of 50%, along with side effect profile may lead to pursuit of other treatment options. 0.5 to 1 mg/kg/day PO, given in 3 divided doses has been recommended by some experts as an initial dose; titrate dosage gradually once weekly. Alternatively, 30 mg PO once daily, then increased to 30 mg PO twice daily has been effective in improving hand tremor. Many patients respond to a dosage of 60 to 80 mg/day PO. Max: 4 mg/kg/day. Dosage may also be taken as needed 30 minutes prior to activities disrupted by essential tremor. Pharmacotherapy should be reserved for patients whose tremor is functionally or socially limiting. Once an optimal dosage is determined, patients may transition to an extended-release formulation of propranolol, to be given once daily. Many patients require larger doses after 1 year of therapy, due to drug tolerance and disease progression.

For the treatment of thyrotoxicosis* and thyroid storm*:
Oral dosage (immediate-release):
Neonates: 1 to 2 mg/kg/day PO divided doses every 6 to 12 hours; occasionally higher doses are required.
Infants: 1 to 2 mg/kg/day PO divided doses every 6 to 12 hours; occasionally higher doses are required.
Children: 2 mg/kg/day PO divided every 6 to 12 hours (Max: 40 mg/dose); occasionally higher doses are required. Flat doses of 20 to 40 mg PO every 6 to 8 hours have been used to treat older children with thyroid storm.
Adolescents: 10 to 40 mg PO every 6 to 8 hours.
Intravenous dosage:
Children and Adolescents: 1 to 3 mg IV as a single dose.

For the treatment of heart failure* (ischemic origin or cardiomyopathy*) usually in conjunction with digoxin, diuretics, or ACE inhibitor therapy:
Oral dosage (immediate-release formulations):
Infants and Children: 0.5 to 1 mg/kg/day PO given in divided doses every 6 to 8 hours has been recommended as an initial dose for sympathetic inhibition. Titrate dosage gradually every 3 to 14 days to a target dose of 2 mg/kg/day PO (range: 1.5 to 3 mg/kg/day). Monitor heart rate and blood pressure.

For the attenuation of hypermetabolism in patients with severe burns*:
Oral dosage (immediate-release formulations):
Infants, Children, and Adolescents: 1 to 4 mg/kg/day PO given in divided doses every 6 hours. Adjust dose as needed to decrease heart rate by 10% to 20% of the admission value or mean age-based population value. 4 mg/kg/day PO was the mean effective dose in an interim analysis of children (n = 90; mean age: 7 +/- 5 years) with more than 30% total body surface area burns. Propranolol therapy began 96 hours postburn and continued for 1 year with few adverse effects. Propranolol therapy significantly reduced heart rate and resting energy expenditure, decreased truncal fat accumulation, prevented bone loss, and improved lean body mass accretion. Maximum dose not clearly defined; severely burned adult patients receive 20 mg PO every 6 hours, with dosage titrated as needed.

For the treatment of atrial fibrillation and/or atrial flutter*:
Intravenous dosage:
Neonates: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.
Infants: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.
Children and Adolescents: 0.01 mg/kg/dose IV every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 3 mg/dose, whichever is less.
Oral dosage (immediate-release):
Neonates: 0.5 to 1 mg/kg/day PO divided every 6 to 8 hours, initially. Increase the dose by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual dose: 2 to 4 mg/kg/day. Max: 16 mg/kg/day or 60 mg/day, whichever is less.
Infants, Children, and Adolescents: 0.5 to 1 mg/kg/day PO divided every 6 to 8 hours, initially. Increase the dose by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual dose: 2 to 4 mg/kg/day. Max: 16 mg/kg/day or 60 mg/day, whichever is less. In older adolescents, 10 to 30 mg/dose PO every 6 to 8 hours may be given.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 16 mg/kg/day PO (Max: 60 mg/day) or 0.15 mg/kg/dose IV (Max: 1 mg/dose) have been used. For hypertension, doses up to 3.5 mg/kg/dose PO or 0.15 mg/kg/dose IV have been used.
-Infants
3.4 mg/kg/day PO for infantile hemangiomas. Safety and efficacy for other indications have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 16 mg/kg/day PO (Max: 60 mg/day) or 0.15 mg/kg/dose IV (Max: 1 mg/dose) have been used. For hypertension, doses up to 3.5 mg/kg/dose PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).
-Children
Children weighing 35 kg or less: Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 60 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).
Children weighing more than 35 kg: Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 120 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).
-Adolescents
Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO (or 120 mg/day PO in older adolescents) or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 120 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used.

Patients with Hepatic Impairment Dosing
Initiate therapy at a reduced dosage and carefully titrate to clinical response; quantitative recommendations are not available.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed.

Intermittent hemodialysis
No dosage adjustments are needed; propranolol is not significantly dialyzable.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Like other beta-adrenergic antagonists, propranolol competes with adrenergic neurotransmitters (e.g., catecholamines) for binding at sympathetic receptor sites. Similar to atenolol and metoprolol, propranolol blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. Pharmacodynamic consequences of beta1-receptor blockade include a decrease in both resting and exercise heart rate and cardiac output, and a decrease in both systolic and diastolic blood pressure. Propranolol may reduce reflex orthostatic hypotension. The fall in cardiac output induced by beta1 effects is often countered by a moderate reflex increase in peripheral vascular resistance that can be magnified by beta2 blockade (unmasked alpha stimulation). As a result, nonselective beta-blocking agents can produce a more modest decrease in (diastolic) blood pressure compared with selective beta1-antagonists. In addition, propranolol also can competitively block beta2-adrenergic responses in the bronchial muscles, potentially inducing bronchospasm.

Infantile Hemangioma
The mechanism of propranolol's effects on infantile hemangiomas is not well understood. Possible molecular mechanisms include vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. Beta-blockers without alpha-antagonistic effects, such as propranolol, inhibit adrenaline-mediated vasodilation, constrict capillaries, and reduce blood flow to the hemangioma. These effects are seen within 1-3 days after propranolol initiation. In addition, propranolol reduces the expression of vascular endothelial growth factor, a signal protein that stimulates the formation of new blood vessels (angiogenesis) to the proliferating hemangioma, and inhibits tubulogenesis, impeding the angiogenesis of microvascular endothelial cells. Endothelial cell apoptosis occurs primarily during the involution phase and is accelerated by beta-adrenergic blockade. Cell death is not complete, as partial regrowth of the hemangioma may occur after propranolol discontinuation.

Hypertension
Actions that make propranolol useful in treating hypertension include: 1) a negative chronotropic effect that decreases heart rate at rest and after exercise, 2) a negative inotropic effect that decreases cardiac output, 3) reduction of sympathetic outflow from the CNS, and 4) suppression of renin release from the kidneys. Thus, propranolol, like other beta-blockers, affects blood pressure via multiple mechanisms. In general, beta-blockers without intrinsic sympathomimetic activity (ISA) exert detrimental effects on LVH and the lipid profile.

Portal Hypertension and Variceal Bleeding
Propranolol has been used to treat portal hypertension and to prevent bleeding of esophageal varices. Nonselective beta-blockers decrease portal venous pressure, decrease blood flow in the superior portosystemic collateral circulation, and decrease blood flow in the splanchnic region. Beta-blockade decreases cardiac output reducing hepatic arterial and portal venous perfusion. Activation of unopposed alpha-receptors lead to splanchnic vasoconstriction, thus decreasing portal perfusion.

Migraine
Numerous mechanisms may contribute to the efficacy of propranolol in preventing migraine headaches. Beta-blockade can prevent arterial dilation, inhibit renin secretion, and can interfere with catecholamine-induced lipolysis. A decrease in lipolysis decreases arachidonic acid synthesis and, subsequently, prostaglandin production. Inhibition of platelet aggregation is due to this decrease in prostaglandins and blockade of catecholamine-induced platelet adhesion. Other actions include increased oxygen delivery to tissues and prevention of coagulation during epinephrine release.

Thyrotoxicosis
Propranolol has 2 roles in the treatment of thyrotoxicosis; these actions are determined by the different isomers of propranolol. L-propranolol causes beta-blockade and can ameliorate the symptoms associated with thyrotoxicosis such as tremor, palpitations, anxiety, and heat intolerance. D-propranolol blocks the conversion of T4 to T3, but the therapeutic effect of this action is minimal.

Essential Tremor
Propranolol has been used in the management of hereditary or familial essential tremor. Beta-blockade controls the involuntary, rhythmic and oscillatory movements of essential tremor. Tremor amplitude is reduced, but not the frequency of tremor. The mechanism of action is unclear, but the anti-tremor effect may be mediated by blockade of peripheral beta2-receptor mechanisms.

Pharmacokinetics: Propranolol is administered orally or intravenously. Approximately 90% of circulating propranolol is protein (albumin and alpha1-acid glycoprotein) bound in adult patients. Binding is enantiomer-selective; the S-isomer is preferentially bound to alpha1-glycoprotein and the R-isomer is preferentially bound to albumin. Propranolol is highly lipophilic and readily crosses the blood brain barrier. The Vd in adults is 4 to 5 L/kg. Extensive metabolism occurs in the liver through 3 primary pathways: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. The percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable interpatient variability. The primary metabolites include propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4-hydroxy propranolol. Of these, 4-hydroxy propranolol is the only pharmacologically active metabolite. Metabolites are excreted in the urine. Elimination half-life is 2 to 6 hours in adults.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP2C19, CYP1A2, and P-glycoprotein (P-gp)
In vitro studies have indicated that the CYP2D6 (aromatic hydroxylation, some side-chain oxidation), CYP1A2 (side-chain oxidation), and to a lesser extent CYP2C19 are involved in propranolol metabolism. The metabolite 4-hydroxy propranolol is a weak inhibitor of CYP2D6. Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter p-glycoprotein (P-gp). However, studies suggest P-gp is not dose-limiting for intestinal absorption of propranolol. In healthy subjects, there is no difference in clearance and elimination half-life between CYP2D6 extensive metabolizers and poor metabolizers.


-Route-Specific Pharmacokinetics
Oral Route
Propranolol is almost completely absorbed after oral administration. However, first pass metabolism is extensive and only about 25% reaches systemic circulation.

Immediate-release formulations
Peak plasma concentrations occur within 1 to 4 hours after oral administration of immediate-release propranolol. Protein-rich foods increase the bioavailability of propranolol by approximately 50% but do not affect the time to peak concentration or half-life.

Sustained-release formulations (e.g., Inderal LA)
Sustained-release propranolol delivers active drug at a controlled and predictable rate. Peak plasma concentrations occur 6 hours after administration. Greater hepatic metabolism and slower rate of absorption result in an AUC that is approximately 60% to 65% of an AUC for a comparable daily dose of immediate-release propranolol. With sustained-release propranolol, plasma concentrations remain constant for approximately 12 hours before they decline exponentially. Elimination half-life is 10 hours. The effect of food on bioavailability has not been investigated.

Extended-release formulations (e.g., Innopran XL)
Peak plasma concentrations of extended-release propranolol are dose-proportional and occur 12 to 14 hours after administration. Elimination half-life is 8 hours. During single-dose, food-effect studies, high-fat meals increased Tmax from 11.5 hours to 15.4 hours in healthy adult subjects, with no effect on AUC.

Intravenous Route
Intravenous propranolol has a distribution half-life of 5 to 10 minutes. Onset of activity occurs within 5 minutes of administration.


-Special Populations
Pediatrics
Neonates
Protein binding of propranolol is approximately 70% in neonates. In a pharmacokinetic study of 36 neonates (mean gestational age 28 weeks; range: 23 to 42 weeks), patients were treated with high dose [HD] (n = 28; 0.5 mg/kg/dose PO every 6 hours) or low dose [LD] (n = 8; 0.25 mg/kg/dose PO every 6 hours) propranolol. All patients received propranolol administered by mouth or orogastric tube as a syrup shortly after a meal. As observed in children and adults, neonates displayed considerable interpatient variability in plasma propranolol concentrations in patients receiving the same dose; in neonates such variability may be a consequence of hepatic immaturity and a variable first pass effect. Drug plasma concentrations appeared to be directly related to the propranolol dose, suggesting good oral bioavailability. Mean peak plasma concentration (Cmax) was 71.7 +/- 29.8 ng/mL in the HD group and 33.9 +/- 19.1 ng/mL in the LD group; mean AUC was 364.7 +/- 150.2 ng/mL and 161.3 +/- 88.3 ng/mL in the HD and LD groups, respectively. Mean Tmax was 2.6 +/- 0.9 hours in the HD group and 2.3 +/- 0.8 hours in the LD group. Half-life was similar in both groups (HD = 14.9 +/- 4.3 hours; LD = 15.9 +/- 6.1 hours), but significantly prolonged compared to adults, most likely explained by hepatic immaturity in the neonate. Mean plasma clearance was 27.2 +/- 13.9 mL/kg/minute in the HD group and 31.3 mL/kg/minute in the LD group.

Infants
Pharmacokinetics of propranolol were evaluated in a multiple dose 12-week study of infants with hemangioma (n = 23; age range: 35 to 150 days). Propranolol was initiated at 1.2 mg/kg/day PO and titrated at weekly intervals to a target dose of 3.4 mg/kg/day PO, divided into twice daily dosing. Plasma propranolol concentrations were dose-proportional in the range studied. At target dose steady state, peak plasma concentrations were observed within 2 hours. Clearance (2.7 L/kg/hour in infants younger than 90 days and 3.3 L/kg/hour in infants older than 90 days) was similar to that in adults when adjusted for body weight. Median elimination half-life was 3.5 hours. The plasma concentration of 4-hydroxy propranolol was approximately 5% of total plasma exposure of propranolol. In a pharmacokinetic study of cyanotic children (n = 5) including 1 infant (age: 9 months), mean half-life of propranolol was 4.9 +/- 1 hours (range: 3.9 to 6.4 hours). Mean half-life for the active metabolite 4-hydroxy propranolol was 6.3 +/- 1.1 hours (range: 5.2 to 7.5 hours). Investigators found no correlation between half-life and age.

Children and Adolescents
The extent of propranolol protein binding in children and adolescents (age 6 to 15 years) is similar to that of adults. In a pharmacokinetic study of cyanotic infants and children (n = 5), ages 9 months to 6 years old, mean half-life for propranolol was 4.9 +/- 1 hours (range: 3.9 to 6.4 hours). Mean half-life for the active metabolite 4-hydroxy propranolol was 6.3 +/- 1.1 hours (range: 5.2 to 7.5 hours). Investigators found no correlation between half-life and age.

Hepatic Impairment
Propranolol is extensively metabolized in the liver. Adult patients with chronic liver disease have decreased clearance, increased Vd, decreased protein-binding, and wide variation in half-life when compared to normal subjects. In a small study (n = 16) of adult patients, those with cirrhosis had a 3-fold increase of unbound propranolol at steady state and a nearly 3-fold increase in half-life compared to healthy subjects.

Renal Impairment
Delayed oral absorption, increased peak plasma concentrations, and decreased plasma clearance have been reported in patients with renal failure. After a single oral dose of propranolol 40 mg, peak plasma concentrations were 161 ng/ml, 47 ng/ml, and 26 ng/ml in adult chronic renal failure, regularly dialyzed, and healthy subjects, respectively. In patients with chronic renal failure, down-regulation of hepatic CYP450 activity results in decreased drug metabolism. Additionally, fecal elimination of propranolol increases in patients with renal dysfunction to compensate for decreased renal excretory processes.

Ethnic Differences
Limited data are available in pediatric patients. African-Americans appear to have increased propranolol clearance, and Chinese patients may have higher unbound propranolol concentrations as compared to Caucasians. In a study of 12 Caucasian and 13 African-American adult males, clearance of both enantiomers was increased in the African-American group. Reported increase in clearance was 76% for the R(+) enantiomer and 53% for the S(-) enantiomer. In another study, Chinese adult patients had a greater proportion (18-45% higher) of unbound plasma propranolol compared to Caucasians; this difference is most likely associated with lower plasma concentrations of alpha1-acid glycoprotein.