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Propranolol
hydrochloride is a synthetic beta-adrenergic receptor blocking agent
chemically described as
(+)-1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its
structural formula is:
Propranolol
hydrochloride is a stable, white, crystalline solid which is readily
soluble in water and ethanol. Its molecular weight is 295.80.
Propranolol
hydrochloride injection is available as a sterile injectable solution
for intravenous administration. Each mL contains 1 mg of propranolol
hydrochloride in Water for Injection. The pH is adjusted with citric
acid.
Propranolol
is a nonselective beta-adrenergic receptor blocking agent
possessing no other autonomic nervous system activity. It
specifically competes with beta-adrenergic receptor stimulating
agents for available receptor sites. When access to
beta-receptor sites is blocked by propranolol, chronotropic,
inotropic, and vasodilator responses to beta-adrenergic
stimulation are decreased proportionately. At doses greater than
required for beta blockade, propranolol also exerts a
quinidine-like or anesthetic-like membrane action, which affects
the cardiac action potential. The significance of the membrane
action in the treatment of arrhythmias is uncertain.
The effects
of propranolol are due to selective blockade of beta-adrenergic
receptors, leaving alpha-adrenergic responses intact. There are
two well-characterized subtypes of beta receptors (beta
1 and beta2); propranolol interacts with
both subtypes equally. Beta1-adrenergic receptors are
found primarily in the heart. Blockade of cardiac
beta1-adrenergic receptors leads to a decrease in the
activity of both normal and ectopic pacemaker cells and a
decrease in A-V nodal conduction velocity. All of these actions
can contribute to antiarrhythmic activity and control of
ventricular rate during arrhythmias. Blockade of cardiac
beta1-adrenergic receptors also decreases the
myocardial force of contraction and may provoke cardiac
decompensation in patients with minimal cardiac reserve.
Beta2-adrenergic receptors are found predominantly in
smooth muscle—vascular, bronchial, gastrointestinal
and genitourinary. Blockade of these receptors results in
constriction. Clinically, propranolol may exacerbate respiratory
symptoms in patients with obstructive pulmonary diseases such as
asthma and emphysema (see CONTRAINDICATIONS and WARNINGS ).
Propranolol’s beta blocking effects are attributable
to its S(-) enantiomer.
Propranolol has a distribution half-life (T½ alpha) of 5-10 minutes and a
volume of distribution of about 4 to 5 L/kg.
Approximately 90% of circulating propranolol is bound to
plasma proteins. The binding is enantiomer-selective.
The S-isomer is preferentially bound to
alpha1 glycoprotein and the R-isomer is
preferentially bound to albumin.
The
elimination half-life (T½ beta) is
between 2 and 5.5 hours. Propranolol is extensively
metabolized with most metabolites appearing in the
urine. The major metabolites include propranolol
glucuronide, naphthyloxylactic acid, and glucuronic acid
and sulfate conjugates of 4-hydroxy propranolol.
Following single-dose intravenous administration,
side-chain oxidative products account for approximately
40% of the metabolites, direct conjugation products
account for approximately 45-50% of metabolites, and
ring oxidative products account for approximately 10-15%
of metabolites. Of these, only the primary ring
oxidative product (4-hydroxypropranolol) possesses
beta-adrenergic receptor blocking activity.
In
vitro studies have indicated that the aromatic
hydroxylation of propranolol is catalyzed mainly by
polymorphic CYP2D6. Side-chain oxidation is mediated
mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy
propranolol is a weak inhibitor of CYP2D6.
As
propranolol concentration increases, so does its beta-blocking
effect, as evidenced by a reduction in exercise-induced
tachycardia (n=6 normal volunteers).
The
pharmacokinetics of propranolol have not been
investigated in patients under 18 years of age.
Propranolol injection is not recommended for treatment
of cardiac arrhythmias in pediatric
patients.
Elevated propranolol plasma concentrations, a longer
mean elimination half-life (254 vs. 152 minutes), and
decreased systemic clearance (8 vs. 13 mL/kg/min) have
been observed in elderly subjects when compared to young
subjects. However, the apparent volume of distribution
seems to be similar in elderly and young subjects. These
findings suggest that dose adjustment of propranolol
injection may be required for elderly patients (see
PRECAUTIONS ).
Intravenously administered propranolol was evaluated in
5 women and 6 men. When adjusted for weight, there were
no gender-related differences in elimination half-life,
volume of distribution, protein binding, or systemic
clearance.
In
a study of intravenously administered propranolol, obese
subjects had a higher AUC (161 versus 109
hr·µg/L) and lower total clearance
than did non-obese subjects. Propranolol plasma protein
binding was similar in both groups.
The
pharmacokinetics of propranolol and its metabolites were
evaluated in 15 subjects with varying degrees of renal
function after propranolol administration via the
intravenous and oral routes. When compared with normal
subjects, an increase in fecal excretion of propranolol
conjugates was observed in patients with increased renal
impairment. Propranolol was also evaluated in 5 patients
with chronic renal failure, 6 patients on regular
dialysis, and 5 healthy subjects, following a single
oral dose of 40 mg of propranolol. The peak plasma
concentrations (Cmax) of propranolol in the
chronic renal failure group were 2- to 3-fold higher
(161 ng/mL) than those observed in the dialysis patients
(47 ng/mL) and in the healthy subjects (26 ng/mL).
Propranolol plasma clearance was also reduced in the
patients with chronic renal failure.
Chronic renal failure has been associated with a
decrease in drug metabolism via downregulation of
hepatic cytochrome P450 activity.
Propranolol is extensively metabolized by the liver. In
a study conducted in 6 normal subjects and 20 patients
with chronic liver disease, including hepatic cirrhosis,
40 mg of R-propranolol was administered intravenously.
Compared to normal subjects, patients with chronic liver
disease had decreased clearance of propranolol,
increased volume of distribution, decreased
protein-binding, and considerable variation in
half-life. Caution should be exercised when propranolol
is used in this population. Consideration should be
given to lowering the dose of intravenous propranolol in
patients with hepatic insufficiency (see PRECAUTIONS ).
No
pharmacokinetic changes were observed in hyperthyroid or
hypothyroid patients when compared to their
corresponding euthyroid state. Dosage adjustment does
not seem necessary in either patient population based on
pharmacokinetic findings.
Because propranolol’s metabolism involves
multiple pathways in the cytochrome P-450 system
(CYP2D6, 1A2, 2C19), administration of propranolol with
drugs that are metabolized by, or affect the activity
(induction or inhibition) of one or more of these
pathways may lead to clinically relevant drug
interactions (see PRECAUTIONS, Drug
Interactions ).
Blood levels of propranolol may be increased by
administration of propranolol with substrates or
inhibitors of CYP2D6, such as amiodarone, cimetidine,
delavirdine, fluoxetine, paroxetine, quinidine, and
ritonavir. No interactions were observed with either
ranitidine or lansoprazole.
Blood levels of propranolol may be increased by
administration of propranolol with substrates or
inhibitors of CYP1A2, such as imipramine, cimetidine,
ciprofloxacin, fluvoxamine, isoniazid, ritonavir,
theophylline, zileuton, zolmitriptan, and
rizatriptan.
Blood levels of propranolol may be increased by
administration of propranolol with substrates or
inhibitors of CYP2C19, such as fluconazole, cimetidine,
fluoxetine, fluvoxamine, teniposide, and tolbutamide. No
interaction was observed with omeprazole.
Blood levels of propranolol may be decreased by
administration of propranolol with inducers such as
rifampin and ethanol. Cigarette smoking also induces
hepatic metabolism and has been shown to increase up to
100% the clearance of propranolol, resulting in
decreased plasma concentrations.
The AUC of propafenone is increased by more
than 200% with co-administration of propranolol.
The metabolism of propranolol is reduced by
co-administration of quinidine, leading to a 2-
to 3-fold increased blood concentrations and
greater beta-blockade.
The metabolism of lidocaine is inhibited by
co-administration of propranolol, resulting in a
25% increase in lidocaine
concentrations.
The mean Cmax and AUC of
propranolol are increased respectively, by 50%
and 30% by co-administration of nisoldipine and
by 80% and 47%, by co-administration of
nicardipine.
The mean values of Cmax and AUC of
nifedipine are increased by 64% and 79%,
respectively, by co-administration of
propranolol.
Propranolol does not affect the
pharmacokinetics of verapamil and norverapamil.
Verapamil does not affect the pharmacokinetics
of propranolol.
Administration of zolmitriptan or rizatriptan
with propranolol resulted in increased
concentrations of zolmitriptan (AUC increased by
56% and Cmax by 37%) or rizatriptan
(the AUC and Cmax were increased by
67% and 75%, respectively).
Co-administration of theophylline with
propranolol decreases theophylline clearance by
33% to 52%.
Propranolol can inhibit the metabolism of
diazepam, resulting in increased concentrations
of diazepam and its metabolites. Diazepam does
not alter the pharmacokinetics of propranolol.
The pharmacokinetics of oxazepam, triazolam,
lorazepam, and alprazolam are not affected by
co-administration of propranolol.
Co-administration of propranolol at doses
greater than or equal to 160 mg/day resulted in
increased thioridazine plasma concentrations
ranging from 50% to 370% and increased
thioridazine metabolites concentrations ranging
from 33% to 210%.
Co-administration of chlorpromazine with
propranolol resulted in increased plasma levels
of both drugs (70% increase in propranolol
concentrations).
Co-administration of propranolol with
cimetidine, a non-specific CYP450 inhibitor,
increased propranolol concentrations by about
40%. Co-administration with aluminum hydroxide
gel (1200 mg) resulted in a 50% decrease in
propranolol concentrations.
Co-administration of metoclopramide with
propranolol did not have a significant effect on
propranolol’s
pharmacokinetics.
Co-administration of cholesteramine or
colestipol with propranolol resulted in up to
50% decrease in propranolol concentrations.
Co-administration of propranolol with
lovastatin or pravastatin decreased 20% to 25%
the AUC of both, but did not alter their
pharmacodynamics. Propranolol did not have an
effect on the pharmacokinetics of
fluvastatin.
Concomitant administration of propranolol and
warfarin has been shown to increase warfarin
bioavailability and increase prothrombin
time.
In a series of 225
patients with supraventricular (n=145), ventricular (n=69), or both
(n=11) arrythmias resistant to digitalis, intravenous propranolol
hydrochloride was administered in single doses, averaging 1 to 5 mg.
Approximately one-quarter of the patients with supraventricular
arrhythmias (generally those with sinus or atrial tachycardia) reverted
to normal sinus rhythm. About one-half had symptoms ameliorated either
by a decrease in ventricular rate or an attenuation of frequency or
severity of paroxysmal attacks.
Approximately
one-half of patients with ventricular arrhythmias (generally those with
frequent PVCs) reverted to normal sinus rhythm or responded with a
reduction in ventricular rate.
Similar findings
were seen in a series of 25 Bantu patients with atrial fibrillation
(n=16), sinus tachycardia (n=5), and multifocal ventricular
extrasystoles (n=9).
In another series,
7 of 8 patients with digitalis-related tachyarrhythmia had ventricular
rate decreases after intravenous propranolol. Similarly limited clinical
experience has shown that intravenous propranolol will slow the
ventricular rate in patients with Wolff-Parkinson-White syndrome or with
tachycardia associated with thyrotoxicosis.
Onset of activity
is usually within five minutes.
Intravenous
administration is usually reserved for life-threatening
arrhythmias or those occurring under anesthesia.
Propranolol is
contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and
greater than first-degree block; 3) bronchial asthma; and 4) in patients
with known hypersensitivity to propranolol hydrochloride.
Sympathetic
stimulation may be a vital component supporting circulatory
function in patients with congestive heart failure, and its
inhibition by beta blockade may precipitate more severe failure.
Although beta-blockers should be avoided in overt congestive
heart failure, some have been shown to be highly beneficial when
used with close follow-up in patients with a history of failure
who are well compensated and are receiving additional therapies,
including diuretics as needed. Beta-adrenergic blocking agents
do not abolish the inotropic action of digitalis on heart
muscle.
In general,
patients with bronchospastic lung disease should not receive
beta blockers. Propranolol should be administered with caution
in this setting since it may block bronchodilation produced by
endogenous and exogenous catecholamine stimulation of
beta-receptors.
The
necessity or desirability of withdrawal of beta-blocking therapy
prior to major surgery is controversial. It should be noted,
however, that the impaired ability of the heart to respond to
reflex adrenergic stimuli in propranolol-treated patients might
augment the risks of general anesthesia and surgical procedures.
Propranolol
is a competitive inhibitor of beta-receptor agonists, and its
effects can be reversed by administration of such agents, e.g.,
dobutamine or isoproterenol. However, such patients may be
subject to protracted severe hypotension.
Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes)
of acute hypoglycemia, especially in labile insulin-dependent
diabetics. In these patients, it may be more difficult to adjust
the dosage of insulin.
Propranolol
therapy, particularly in infants and children, diabetic or not,
has been associated with hypoglycemia especially during fasting,
as in preparation for surgery. Hypoglycemia has been reported
after prolonged physical exertion and in patients with renal
insufficiency.
Beta-adrenergic blockade may mask certain clinical signs of
hyperthyroidism. Therefore, abrupt withdrawal of propranolol may
be followed by an exacerbation of symptoms of hyperthyroidism,
including thyroid storm. Propranolol may change thyroid-function
tests, increasing T4 and reverse T3, and
decreasing T3.
Beta-adrenergic blockade in patients with Wolff-Parkinson-White
syndrome and tachycardia has been associated with severe
bradycardia requiring treatment with a pacemaker. In one case
this resulted after an initial 5 mg dose of intravenous
propranolol.
Propranolol
should be used with caution in patients with impaired hepatic or
renal function. Propranolol is not indicated for the treatment
of hypertensive emergencies.
Beta-adrenergic receptor blockade can cause reduction of
intraocular pressure. Patients should be told that propranolol
might interfere with the glaucoma screening test. Withdrawal may
lead to a return of elevated intraocular pressure.
Risk of
anaphylactic reaction. While taking beta blockers, patients with
a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be
unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
There have been reports of exacerbation of angina and,
in some cases, myocardial infarction, following abrupt
discontinuance of propranolol therapy. Therefore, when
discontinuance of propranolol is planned, the dosage
should be gradually reduced over at least a few weeks,
and the patient should be cautioned against interruption
or cessation of therapy without a physician’s
advice. If propranolol therapy is interrupted and
exacerbation of angina occurs, it is usually advisable
to reinstitute propranolol therapy and take other
measures appropriate for the management of angina
pectoris. Since coronary artery disease may be
unrecognized, it may be prudent to follow the above
advice in patients considered at risk of having occult
atherosclerotic heart disease who are given propranolol
for other indications.
In patients
with hypertension, use of propranolol has been associated with
elevated levels of serum potassium, serum transaminases and
alkaline phosphatase. In severe heart failure, the use of
propranolol has been associated with increases in Blood Urea
Nitrogen.
Caution
should be exercised when propranolol is administered with drugs
that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways.
Co-administration of such drugs with propranolol may lead to
clinically relevant drug interactions and changes in its
efficacy and/or toxicity (see CLINICAL
PHARMACOLOGY, Drug Interactions ).
Propafenone has negative inotropic and
beta-blocking properties that can be additive to
those of propranolol.
Quinidine increases the concentration of
propranolol and produces a greater degree of
clinical beta-blockade and may cause postural
hypotension.
Disopyramide is a Type I antiarrhythmic drug
with potent negative inotropic and chronotropic
effects and has been associated with severe
bradycardia, asystole and heart failure when
administered with propranolol.
Amiodarone is an antiarrhythmic agent with
negative chronotropic properties that may be
additive to those seen with propranolol.
The clearance of lidocaine is reduced when
administered with propranolol. Lidocaine
toxicity has been reported following
coadministration with propranolol.
Caution should be exercised when administering
propranolol with drugs that slow A-V nodal
conduction, e.g. digitalis, lidocaine and
calcium channel blockers.
Caution should be exercised when patients
receiving a beta-blocker are administered a
calcium-channel-blocking drug with negative
inotropic and/or chronotropic effects. Both
agents may depress myocardial contractility or
atrioventricular conduction.
There have been reports of significant
bradycardia, heart failure, and cardiovascular
collapse with concurrent use of verapamil and
beta-blockers.
Co-administration of propranolol and diltiazem
in patients with cardiac disease has been
associated with bradycardia, hypotension, high
degree heart block, and heart
failure.
When combined with beta-blockers, ACE
inhibitors can cause hypotension, particularly
in the setting of acute myocardial infarction.
ACE inhibitors have been reported to increase
bronchial hyperreactivity when administered with
propranolol.
The antihypertensive effects of clonidine may
be antagonized by beta-blockers. Propranolol
should be administered cautiously to patients
withdrawing from clonidine.
Prazosin has been associated with prolongation
of first dose hypotension in the presence of
beta-blockers.
Postural hypotension has been reported in
patients taking both beta-blockers and terazosin
or doxazosin.
Patients receiving catecholamine-depleting
drugs, such as reserpine, with propranolol
should be closely observed for excess reduction
of resting sympathetic nervous activity, which
may result in hypotension, marked bradycardia,
vertigo, syncopal attacks, or orthostatic
hypotension. Administration of reserpine with
propranolol may also potentiate
depression.
Patients on long-term therapy with propranolol
may experience uncontrolled hypertension if
administered epinephrine as a consequence of
unopposed alpha-receptor stimulation.
Epinephrine is therefore not indicated in the
treatment of propranolol overdose (see OVERDOSAGE ).
Propranolol is a competitive inhibitor of
beta-receptor agonists, and its effects can be
reversed by administration of such agents, e.g.,
dobutamine or isoproterenol. Also, propranolol
may reduce sensitivity to dobutamine stress
echocardiography in patients undergoing
evaluation for myocardial ischemia.
Nonsteroidal anti-inflammatory drugs (NSAIDS)
have been reported to blunt the antihypertensive
effect of beta-adrenoreceptor blocking agents.
Administration of indomethacin with propranolol
may reduce the efficacy of propranolol in
reducing blood pressure and heart
rate.
The hypotensive effects of MAO inhibitors or
tricyclic antidepressants may be exacerbated
when administered with beta-blockers by
interfering with the beta blocking activity of
propranolol.
Methoxyflurane and trichloroethylene may
depress myocardial contractility when
administered with propranolol.
Administration of propranolol with warfarin
increases the concentration of warfarin.
Therefore, the prothrombin time should be
monitored.
Hypotension and cardiac arrest have been
reported with the concomitant use of propranolol
and haloperidol.
Thyroxine may result in a lower than expected T3 concentration when used
concomitantly with propranolol.
In dietary
administration studies in which mice and rats were treated with
propranolol hydrochloride for up to 18 months at doses of up to
150 mg/kg/day, there was no evidence of drug-related
tumorigenesis. On a body surface area basis, this dose in the
mouse and rat is, respectively, about equal to and about twice
the maximum recommended human oral daily dose (MRHD) of 640 mg
propranolol hydrochloride. In a study in which both male and
female rats were exposed to propranolol hydrochloride in their
diets at concentrations of up to 0.05% (about 50 mg/kg body
weight and less than the MRHD), from 60 days prior to mating and
throughout pregnancy and lactation for two generations, there
were no effects on fertility. Based on differing results from
Ames Tests performed by different laboratories, there is
equivocal evidence for a genotoxic effect of propranolol
hydrochloride in bacteria ( S.
typhimurium strain TA 1538).
In
a series of reproductive and developmental toxicology
studies, propranolol hydrochloride was given to rats by
gavage or in the diet throughout pregnancy and
lactation. At doses of 150 mg/kg/day, but not at doses
of 80 mg/kg/day (equivalent to the MRHD on a body
surface area basis), treatment was associated with
embryotoxicity (reduced litter size and increased
resorption rates) as well as neonatal toxicity (deaths).
Propranolol hydrochloride also was administered (in the
feed) to rabbits (throughout pregnancy and lactation) at
doses as high as 150 mg/kg/day (about 5 times the
maximum recommended human oral daily dose). No evidence
of embryo or neonatal toxicity was noted.
There are no adequate and well-controlled studies in
pregnant women. Intrauterine growth retardation has been
reported for neonates whose mothers received propranolol
hydrochloride during pregnancy. Neonates whose mothers
received propranolol hydrochloride at parturition have
exhibited bradycardia, hypoglycemia, and respiratory
depression. Adequate facilities for monitoring such
infants at birth should be available. Propranolol should
be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Propranolol
is excreted in human milk. Caution should be exercised when
propranolol is administered to a nursing woman.
Safety and
effectiveness of propranolol in pediatric patients have not been
established.
Clinical
studies of intravenous propranolol did not include sufficient
numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Elderly subjects have
decreased clearance and a longer mean elimination half-life.
These findings suggest that dose adjustment of propranolol
injection may be required for elderly patients (see CLINICAL
PHARMACOLOGY, Special Populations, Geriatric ). In
general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of the decreased hepatic, renal
or cardiac function, and of concomitant disease or other drug
therapy.
Propranolol
is extensively metabolized by the liver. Compared to normal
subjects, patients with chronic liver disease have decreased
clearance of propranolol, increased volume of distribution,
decreased protein-binding and considerable variation in half
life. Consideration should be given to lowering the dose of
intravenously administered propranolol in patients with hepatic
insufficiency.
In a series of 225
patients, there were 6 deaths (see CLINICAL
STUDIES ). Cardiovascular events (hypotension, congestive
heart failure, bradycardia, and heart block) were the most common. The
only other event reported by more than one patient was nausea.
Other adverse
events for intravenous propranolol, reported during post-marketing
surveillance include cardiac arrest, dyspnea, and cutaneous ulcers.
The following
adverse events have been reported with use of formulations of sustained-
or immediate-release oral propranolol and may be expected with
intravenous propranolol.
Bradycardia; congestive heart failure; intensification of AV
block; hypotension; paresthesia of hands; thrombocytopenic
purpura; arterial insufficiency, usually of the Raynaud
type.
Light-headedness; mental depression manifested by insomnia,
lassitude, weakness, fatigue; reversible mental depression
progressing to catatonia; visual disturbances; hallucinations;
vivid dreams; an acute reversible syndrome characterized by
disorientation for time and place, short-term memory loss,
emotional lability, slightly clouded sensorium, and decreased
performance on neuropsychometrics. For immediate-release
formulations, fatigue, lethargy, and vivid dreams appear dose
related.
Nausea,
vomiting, epigastric distress, abdominal cramping, diarrhea,
constipation, mesenteric arterial thrombosis, ischemic
colitis.
Pharyngitis
and agranulocytosis; erythematous rash, fever combined with
aching and sore throat; laryngospasm, and respiratory
distress.
Bronchospasm.
Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic
purpura.
In
extremely rare instances, systemic lupus erythematosus has been
reported.
Alopecia,
LE-like reactions, psoriaform rashes, dry eyes, male impotence,
and Peyronie’s disease have been reported rarely.
Oculomucocutaneous reactions involving the skin, serous
membranes and conjunctivae reported for a beta-blocker
(practolol) have not been associated with
propranolol.
Propranolol is not
significantly dialyzable. In the event of overdose or exaggerated
response, the following measures should be employed:
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 50-150 mcg/kg intravenously
followed by continuous drip of 1-5 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.
The
electrocardiogram, pulse, blood pressure, neurobehavioral status and
intake and output balance must be monitored. Isoproterenol and
aminophylline may be useful for bronchospasm.
Parenteral drug
products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container
permit.
The usual dose is 1
to 3 mg administered under careful monitoring, such as
electrocardiography and central venous pressure. The rate of
administration should not exceed 1 mg (1 mL) per minute to diminish the
possibility of lowering blood pressure and causing cardiac standstill.
Sufficient time should be allowed for the drug to reach the site of
action even when a slow circulation is present. If necessary, a second
dose may be given after two minutes. Thereafter, additional drug should
not be given in less than four hours. Additional propranolol
hydrochloride should not be given when the desired alteration in rate or
rhythm is achieved.
Transfer to oral
therapy as soon as possible.
Each mL contains 1
mg of propranolol hydrochloride in Water for Injection. The pH is
adjusted with citric acid. Supplied as: 1 mL ampuls in boxes of 10 (NDC
10019-145-01).
Store at controlled room temperature
20° to 25°C (68° to 77°F).
Protect from freezing or excessive heat.
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015
USA
For Product Inquiry
1 800 ANA DRUG (1-800-262-3784)
MLT-01594/2.0
FDA LABEL
GENERIC: Propranolol MFR: Baxter Healthcare Corporation
1 Ml Propranolol Hydrochloride 1 Mg/ml Injection
Table of Contents
DESCRIPTION
CLINICAL PHARMACOLOGY
General
Mechanism of Action
Pharmacokinetics And Drug Metabolism
Distribution
Metabolism and Elimination
Pharmacodynamics
Special Populations
Pediatric
Geriatric
Gender
Obesity
Renal Insufficiency
Hepatic Insufficiency
Thyroid Dysfunction
Drug Interactions
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes
Substrates or Inhibitors of CYP2D6
Substrates or Inhibitors of CYP1A2
Substrates or Inhibitors of CYP2C19
Inducers of Hepatic Drug Metabolism
Cardiovascular Drugs
Antiarrhythmics
Calcium Channel Blockers
Non-Cardiovascular Drugs
Migraine Drugs
Theophylline
Benzodiazepines
Neuroleptic Drugs
Anti-Ulcer Drugs
Lipid Lowering Drugs
Warfarin
CLINICAL STUDIES
INDICATIONS AND USAGE
Cardiac Arrhythmias
- Supraventricular arrhythmiasIntravenous propranolol is indicated for the short-term treatment of supraventricular tachycardia, including Wolff-Parkinson-White syndrome and thyrotoxicosis, to decrease ventricular rate. Use in patients with atrial flutter or atrial fibrillation should be reserved for arrythmias unresponsive to standard therapy or when more prolonged control is required. Reversion to normal sinus rhythm has occasionally been observed, predominantly in patients with sinus or atrial tachycardia.
- Ventricular tachycardias With the exception of those induced by catecholamines or digitalis, propranolol is not the drug of first choice. In critical situations when cardioversion techniques or other drugs are not indicated or are not effective, propranolol may be considered. If, after consideration of the risks involved, propranolol is used, it should be given intravenously in low dosage and very slowly, as the failing heart requires some sympathetic drive for maintenance of myocardial tone. (See ). Some patients may respond with complete reversion to normal sinus rhythm, but reduction in ventricular rate is more likely. Ventricular arrhythmias do not respond to propranolol as predictably as do the supraventricular arrhythmias. Intravenous propranolol is indicated for the treatment of persistent premature ventricular extrasystoles that impair the well-being of the patient and do not respond to conventional measures.
- Tachyarrhythmias of digitalis intoxicationIntravenous propranolol is indicated to control ventricular rate in life-threatening digitalis-induced arrhythmias. Severe bradycardia may occur. (See ).
- Resistant tachyarrhythmias due to excessive catecholamine action during anesthesia Intravenous propranolol is indicated to abolish tachyarrhythmias due to excessive catecholamine action during anesthesia when other measures fail. These arrhythmias may arise because of release of endogenous catecholamines or administration of catecholamines. All general inhalation anesthetics produce some degree of myocardial depression. Therefore, when propranolol is used to treat arrhythmias during anesthesia, it should be used with extreme caution, usually with constant monitoring of the ECG and central venous pressure. (See ).