INNOPRAN XL® (propranolol hydrochloride)

INNOPRAN XL® (propranolol hydrochloride)

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INNOPRAN XL® (propranolol hydrochloride)

INNOPRAN XL contains propranolol hydrochloride, a nonselective, beta-adrenergic receptor blocking agent for oral administration, as an extended-release product. INNOPRAN XL is available as 80 mg and 120 mg capsules which contain sustained-release beads. Each of the beads contains propranolol hydrochloride and is coated with dual membranes. These membranes are designed to retard release of propranolol hydrochloride for several hours after ingestion followed by the sustained release of propranolol.

The active ingredient in INNOPRAN XL is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride.

Propranolol hydrochloride is a stable, white, crystalline solid, which is readily soluble in water and ethanol. Its molecular weight is 295.81. Each capsule for oral administration contains sugar spheres, ethylcellulose, povidone, hypromellose phthalate, diethyl phthalate, hypromellose, polyethylene glycol, gelatin, titanium dioxide, and black iron oxide. In addition, INNOPRAN XL 120 mg capsules contain yellow iron oxide.

Indications and usage

INNOPRAN XL is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including beta-blockers.

Mechanism of Action

The mechanism of the antihypertensive effect of propranolol has not been established. Among factors that contribute to the antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use. Effects of propranolol on plasma volume appear to be minor and somewhat variable.

Dosage and administration

INNOPRAN XL should be administered once daily at bedtime and should be taken consistently either on an empty stomach or with food.Initiate dosing at 80 mg and titrate to 120 mg daily as needed for blood pressure control. Doses above 120 mg have no additional effects on blood pressure. Full antihypertensive response is usually achieved within 2 to 3 weeks.

Contraindications

  • Cardiogenic shock and decompensated heart failure.
  • Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place.
  • Bronchial asthma.
  • Hypersensitivity to propranolol or any of the components of INNOPRAN XL

Warnings and precautions

  • Abrupt cessation may exacerbate myocardial ischemia.
  • May worsen congestive heart failure.
  • Avoid discontinuing therapy prior to major surgery.
  • Diabetes: May mask symptoms of hypoglycemia.
  • Bradycardia.

Adverse reactions

The most commonly reported adverse reactions (≥3% and greater than placebo) included the following: fatigue, dizziness, and constipation

Drug interactions

Warfarin: Warfarin concentrations are increased when administered with propranolol. Monitor prothrombin time accordingly

Propafenone: Co-administration of propranolol increases the plasma concentrations of propafenone. Monitor patients for symptoms of excessive exposure to propafenone including bradycardia and postural hypotension

CYP2D6, CYP1A2 and CYP2C19 Inhibitors: CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine), CYP1A2 inhibitors (e.g., ciprofloxacin, enoxamine, fluvoxamine) and CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) increase exposure to propranolol when co-administered with INNOPRAN XL. Monitor patients for bradycardia and hypotension

CYP1A2 and CYP2C19 Inducers: CYP1A2 inducers (e.g., phenytoin, montelukast, smoking) and CYP2C19 inducers (e.g. rifampin) decrease the plasma levels of propranolol resulting in a loss of efficacy

Cholestyramine and Colestipol: Co-administered cholestyramine or colestipol significantly reduces the plasma concentrations of co-administered propranolol which may result in loss of efficacy.

Adrenergic Agonists: Beta-blockers may antagonize the antihypertensive effects of clonidine, and rebound hypertension may result if clonidine is withdrawn abruptly. If clonidine and a betablocker are co-administered, withdraw the beta-blocker several days before the withdrawal of clonidine.

Alpha Blockers: Co-administration of beta-blockers with alpha-blocker (e.g., prazosin) has been associated with prolongation of first dose hypotension and syncope.

Dobutamine: Propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.

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Antidepressants: The hypotensive effect of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers. Monitor patients for postural hypotension.

Nonsteroidal Anti-Inflammatory Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-adrenoreceptor blocking agents. Monitor blood pressure.

Use in specific populations

Pregnancy: Prolonged experience with propranolol in pregnant women over several decades, based on published interventional and observational studies, has not identified a drug associated risk of major birth defects, miscarriage, or other adverse maternal outcomes. Bradycardia, hypoglycemia, and respiratory depression have been observed with use of beta-blockers, including propranolol, in utero near the time of delivery. There are inconsistent reports of intrauterine growth restriction with beta-blocker use, including propranolol, during pregnancy. Untreated hypertension during pregnancy can lead to serious adverse outcomes for the mother and the fetus

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage) Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Propranolol crosses the placenta. Neonates born to mothers who are receiving propranolol during pregnancy, may be at risk for bradycardia, hypoglycemia, and respiratory depression. Monitor neonates exposed to propranolol during pregnancy and manage accordingly.

Lactation: Propranolol is present in human milk at low levels, but the related risk to a breastfed infant is unknown. There are no data on the effects of propranolol on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INNOPRAN XL and any potential adverse effects on the breastfed child from INNOPRAN XL or from the underlying maternal condition.

Males: Based on the published literature, beta-blockers, including propranolol, may cause erectile dysfunction. In rats, propranolol inhibits spermatogenesis

Pediatric Use: Safety and effectiveness of propranolol in pediatric patients have not been established.

Renal Impairment: The exposure to propranolol is increased in patients with renal impairment. Initiate INNOPRAN XL therapy in patients with impaired renal function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension.

Hepatic Impairment: The exposure to propranolol is increased in patients with hepatic impairment. Initiate INNOPRAN XL therapy in patients with impaired hepatic function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension

Overdosage

Most overdoses of propranolol are mild and respond to supportive care.

Propranolol is not significantly dialyzable.

Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.

Glucagon should be administered as 50 to 150 mcg/kg intravenously followed by continuous drip of 1 to 5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.

Monitor the electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance. Isoproterenol and aminophylline may be used for bronchospasm.

Storage

Store at 25ºC (77ºF); excursions permitted to 15º and 30ºC (59º and 86ºF) [see USP Controlled Room Temperature] in a tightly closed container.

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