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propranolol (Inderal, Inderal LA, InnoPran XL, Hemangeol)

 

Classes: Antidysrhythmics, II; Beta-Blockers, Nonselective; Antianginal Agents; Antimigraine Agents

Dosing and uses of Inderal, Inderal LA (propranolol)

 

Adult dosage forms and strengths

oral solution

  • 20mg/5mL
  • 40mg/5mL

injectable solution

  • 1mg/mL

tablet

  • 10mg
  • 20mg
  • 40mg
  • 60mg
  • 80mg

capsule, extended-release

  • 60mg
  • 80mg
  • 120mg
  • 160mg

 

Hypertension

Immediate release

  • 40 mg PO q12hr initially, increasing every 3-7 days; maintenance: 80-240 mg PO q8-12hr; not to exceed 640 mg/day

Inderal LA

  • 80 mg/day PO initially; maintenance: 120-160 mg/day; not to exceed 640 mg/day

InnoPran XL

  • 80 mg/day PO initially; may be increased every 2-3 weeks until response achieved; maintenance: not to exceed 120 mg/day PO

 

Migraine

Prophylaxis

80 mg/day PO divided q6-8hr initially; may be increased by 20-40 mg/day every 3-4 weeks; not to exceed 160-240 mg/day divided q6-8hr

Inderal LA: 80 mg/day PO; maintenance: 160-240 mg/day

Withdraw therapy if satisfactory response not seen after 6 weeks

 

Angina

80-320 mg/day PO divided q6-12hr

Inderal LA: 80 mg/day PO; not to exceed 320 mg/day

 

Pheochromocytoma

30-60 mg/day PO in divided doses

 

Hypertrophic Subaortic Stenosis

20-40 mg PO q6-8hr

 

Supraventricular Arrhythmia

PO: 10-30 mg q6-8hr

IV: 1-3 mg at 1 mg/min initially; repeat q2-5min to total of 5 mg

Once response or maximum dose achieved, do not give additional dose for at least 4 hours

 

Portal Hypertension

Prevention of variceal bleeding

10-60 mg PO q6-8hr; 10 mg PO q8hr initially; titrate dose to reduce resting heart rate by 25%

 

Essential Tremor

40 mg PO q12hr initially; maintenance: 120-320 mg/day PO divided q8-12hr

 

Antipsychotic-Induced Akathisia

30-120 mg PO q8-12hr

 

Malignant Glioma (Orphan)

Orphan designation for treatment of malignant glioma (plus etodolac)

Sponsor

  • Vicus Therapeutics, LLC; 55 Madison Avenue, Suite 400; Morristown, NJ 07960

 

Esophageal Variceal Bleeding (Off-label)

20-180 mg PO q12hr; adjust to maximum tolerated dose

 

Panic Disorder (Off-label)

40-320 mg/day PO

 

Aggressive Behavior (Off-label)

80-300 mg/day PO

 

Pediatric dosage forms and strengths

oral solution

  • 4.28mg/mL (Hemangeol)
  • 20mg/5mL
  • 40mg/5mL

injectable solution

  • 1mg/mL

tablet

  • 10mg
  • 20mg
  • 40mg
  • 60mg
  • 80mg

capsule, extended-release

  • 60mg
  • 80mg
  • 120mg
  • 160mg

 

Infantile Hemangiomas

Hemangeol: Indicated for treatment of proliferating hemangioma requiring systemic therapy

Initiate treatment at aged 5 weeks to 5 months

Starting dose: 0.6 mg/kg (0.15 mL/kg) PO BID for 1 week, THEN increase dose to 1.1 mg/kg (0.3 mL/kg) BID; after 2 more weeks, increase to maintenance dose of 1.7 mg/kg (0.4 mL/kg) BId

Administration (infantile hemangiomas)

  • Use supplied oral dosing syringe for administration and give directly into the child’s mouth; if necessary, the product may be diluted in a small quantity of milk or fruit juice and given in a baby’s bottle
  • Administer doses at least 9 hr apart during or after feedings
  • To reduce the risk of hypoglycemia, administer during or right after a feeding; skip the dose if the child is not eating or is vomiting
  • Readjust dose periodically as the child's weight increases
  • Monitor HR and BP for 2 hr after initial dose and after increasing dose
  • If hemangiomas recur, treatment may be reinitiated

 

Hypertension (Off-label)

0.5-1 mg/kg/day PO divided q6-12hr initially; increase gradually every 5-7 days; usual range: 2-4 mg/kg/day PO divided q12hr

 

Arrhythmias (Off-label)

PO: 0.5-1 mg/kg/day divided q6-8hr; may be increased every 3-7 days; usual range: 2-6 mg/kg/day; not to exceed 16 mg/kg/day or 60 mg/day

IV: 0.01-0.1 mg/kg over 10 minutes; repeat q6-8hr PRN; not to exceed 1 mg for infants or 3 mg for children

 

Hypercyanotic Spells (Off-label)

PO: 1 mg/kg/day divided q6hr; after 1 week, may be increased by 1 mg/kg/day to maximum of 10-15 mg/kg/day if patient refractory; allow 24 hours between dosing changes

IV: 0.01-0.2 mg/kg over 10 minutes; not to exceed 5 mg

 

Thyrotoxicosis (Off-label)

10-40 mg PO q6hr; adjust dose to effect

 

Geriatric dosage forms and strengths

 

Hypertension

Immediate-release: 40 mg PO q12hr initially, increased every 3-7 days; maintenance: 80-240 mg PO q8-12hr; not to exceed 640 mg/day

Inderal LA: 80 mg/day PO initially; maintenance: 120-160 mg/day; not to exceed 640 mg/day

InnoPran XL: 80 mg/day PO initially; may be increased every 2-3 weeks until response achieved; maintenance: not to exceed 120 mg/day PO

Consider lower initial dose

 

Supraventricular Arrhythmia

PO: 10 mg q6-8hr; may be increased every 3-7 days

IV: 1-3 mg at 1 mg/min initially; repeat q2-5min to total of 5 mg

Once response or maximum dose achieved, do not give additional dose for at least 4 hours

 

Inderal, Inderal LA (propranolol) adverse (side) effects

Frequency not defined

Aggravated congestive heart failure

Bradycardia

Hypotension

Arthropathy

Raynaud phenomenon

Hyper/hypoglycemia

Depression

Fatigue

Insomnia

Paresthesia

Psychotic disorder

Pruritus

Nausea

Vomiting

Hyperlipidemia

Hyperkalemia

Cramping

Bronchospasm

Dyspnea

Pulmonary edema

Respiratory distress

Wheezing

 

Postmarketing Reports

Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid; agranulocytosis, erythematous rash, fever with sore throat

Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, urticaria

Musculoskeletal: Myopathy, myotonia

 

Warnings

Black box warnings

May exacerbate ischemic heart disease after abrupt withdrawaL

Hypersensitivity to catecholamines has been observed during withdrawaL

Exacerbation of angina and, in some cases, myocardial infarction occurrence after abrupt discontinuance

When discontinuing long-term administration of beta blockers (particularly with ischemic heart disease), gradually reduce dose over 1-2 weeks and carefully monitor

If angina markedly worsens or acute coronary insufficiency develops, reinstate beta-blocker administration promptly, at least temporarily (in addition to other measures appropriate for unstable angina)

Warn patients against interruption or discontinuance of beta-blocker therapy without physician advice

Because coronary artery disease is common and may be unrecognized, slowly discontinue beta-blocker therapy, even in patients treated only for hypertension

 

Contraindications

Asthma, COPd

Severe sinus bradycardia or 2°/3° heart block (except in patients with functioning artificial pacemaker)

Cardiogenic shock

Uncompensated congestive heart failure

Hypersensitivity

Overt heart failure

Sick sinus syndrome without permanent pacemaker

Infantile hemangioma

  • Premature infants with corrected age <5 weeks
  • Infants weighing <2 kg
  • Hypersensitivity
  • Asthma or history of bronchospasm
  • Heart rate <80 bpm
  • Greater than first-degree heart block
  • Decompensated heart failure
  • Blood pressure <50/30 mm Hg
  • Pheochromocytoma

 

Cautions

Do not use InnoPran XL in pediatric patients

Long-term beta blocker therapy should not be routinely discontinued before major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures

Use caution in bronchospastic disease, cerebrovascular insufficiency, congestive heart failure, diabetes mellitus, hyperthyroidism/thyrotoxicosis, liver disease, renal impairment, peripheral vascular disease, myasthenic conditions

Sudden discontinuance can exacerbate angina and lead to myocardial infarction

Use in pheochromocytoma

Increased risk of stroke after surgery

Hypersensitivity reactions, including anaphylactic and anaphylactoid reactions, have been reported

Cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported

Exacerbation of myopathy and myotonia has been reported

Less effective than thiazide diuretics in black and geriatric patients

May worsen bradycardia or hypotension; monitor HR and Bp

Avoid beta blockers without alpha1-adrenergic receptor blocking activity in patients with prinzmetal variant angina; unopposed alpha-1 adrenergic receptors may worsen anginal symptoms

May induce or exacerbate psoriasis; cause and effect not established

Prevents the response of endogenous catecholamines to correct hypoglycemia and masks the adrenergic warning signs of hypoglycemia, particularly tachycardia, palpitations, and sweating May cause or worsen bradycardia or hypotension

Infantile hemangiomas and PHACE syndrome

  • By dropping blood pressure, propranolol may increase the risk of stroke in patients with PHACE syndrome who have severe cerebrovascular anomalies
  • Investigate infants with large facial infantile hemangioma for potential arteriopathy associated with PHACE syndrome before therapy

 

Pregnancy and lactation

Pregnancy category: C; intrauterine growth retardation, small placentas, and congenital abnormalities reported, but no adequate and well-controlled studies conducted

Lactation: Use is controversial; an insignificant amount is excreted in breast milk

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Inderal, Inderal LA (propranolol)

Mechanism of action

Nonselective beta adrenergic receptor blocker; competitive beta1 and beta2 receptor inhibition results in decreases in heart rate, myocardial contractility, myocardial oxygen demand, and blood pressure

Class 2 antidysrhythmic

 

Absorption

Bioavailability: 30-70% (food increases bioavailability)

Onset: Hypertension, 2-3 wk; beta blockade, 2-10 min (IV) or 1-2 hr (PO)

Duration: 6-12 hr (immediate release); 24-27 hr (extended release)

Peak plasma time: 1-4 hr (immediate release); 6-14 hr (extended release)

 

Distribution

Protein bound: 68% (newborns); 90% (adults)

Vd: 4 L/kg in adults

 

Metabolism

Metabolized by hepatic P450 enzymes CYP2D6 and CYP1A2

Metabolites: 4-hydroxypropranolol (active)

 

Elimination

Half-life: Children, 3.9-6.4 hr; adults, 3.9-6.4 hr (immediate release) or 8-10 hr (extended release)

Excretion: Urine (96-99%)

Dialyzable: HD: No

 

Administration

IV Incompatibilities

Additive: Bicarbonate

Syringe: Bicarbonate

Y-site: Amphotericin B cholesteryl sulfate, diazoxide

 

IV Compatibilities

Solution: Most common solvents

Additive: Dobutamine, verapamiL

Syringe: Inamrinone, milrinone

Y-site: Alteplase, fenoldopam, gatifloxacin, heparin, hydrocortisone, sodium succinate, inamrinone, linezolid, meperidine, milrinone, morphine, potassium chloride, propofol, tacrolimus, tirofiban, vitamins B and C

 

IV Administration

IV administration rate should not exceed 1 mg/min

IV dose is much smaller than oral dose

Give by direct injection into large vessel or into tubing of free-flowing compatible IV solution

Continuous IV infusion generally is not recommended

 

Storage

Protect injection from light