Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/478
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Propranolol Hydrochloride (Injection)
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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.
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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.
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General: 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.<br/>Mechanism of Action: 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 (betaand beta); propranolol interacts with
both subtypes equally. Beta-adrenergic receptors are
found primarily in the heart. Blockade of cardiac
beta-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
beta-adrenergic receptors also decreases the
myocardial force of contraction and may provoke cardiac
decompensation in patients with minimal cardiac reserve. Beta-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 . Propranolol's beta blocking effects are attributable
to its S(-) enantiomer.<br/>Pharmacokinetics
And Drug Metabolism:<br/>Distribution: Propranolol has a distribution half-life (Talpha) 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
alphaglycoprotein and the R-isomer is
preferentially bound to albumin.<br/>Metabolism
and Elimination: The
elimination half-life (Tbeta) 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.<br/>Pharmacodynamics: As
propranolol concentration increases, so does its beta-blocking
effect, as evidenced by a reduction in exercise-induced
tachycardia (n=6 normal volunteers).<br/>Special Populations:<br/>Pediatric: 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.<br/>Geriatric: 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).<br/>Gender: 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.<br/>Obesity: In
a study of intravenously administered propranolol, obese
subjects had a higher AUC (161 versus 109
hr����g/L) and lower total clearance
than did non-obese subjects. Propranolol plasma protein
binding was similar in both groups.<br/>Renal
Insufficiency: 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 (C) 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.<br/>Hepatic
Insufficiency: 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 .<br/>Thyroid
Dysfunction: 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.<br/>Drug Interactions:<br/>Interactions with Substrates, Inhibitors or Inducers of
Cytochrome P-450 Enzymes: 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).<br/>Substrates
or Inhibitors of CYP2D6: 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.<br/>Substrates
or Inhibitors of CYP1A2: 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.<br/>Substrates
or Inhibitors of CYP2C19: 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.<br/>Inducers of
Hepatic Drug Metabolism: 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.<br/>Cardiovascular Drugs:<br/>Non-Cardiovascular Drugs:
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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.
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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
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General: 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.<br/>Angina
Pectoris: 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 andexacerbation 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.<br/>Clinical Laboratory
Tests: 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.<br/>Drug Interactions: 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).<br/>Cardiovascular Drugs:<br/>Non-Cardiovascular Drugs:<br/>Carcinogenesis and
Mutagenesis and Impairment of Fertility: 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 humanoral 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).<br/>Pregnancy:<br/>Pregnancy
Category C: 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 usedduring pregnancy only if the potential benefit
justifies the potential risk to the fetus.<br/>Nursing Mothers: Propranolol
is excreted in human milk. Caution should be exercised when
propranolol is administered to a nursing woman.<br/>Pediatric Use: Safety and
effectiveness of propranolol in pediatric patients have not been
established.<br/>Geriatric Use: 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.<br/>Hepatic
Insufficiency: 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.
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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.
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Propranolol Hydrochloride
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Propranolol Hydrochloride (Injection)
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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.<br/>Cardiovascular: Bradycardia; congestive heart failure; intensification of AV
block; hypotension; paresthesia of hands; thrombocytopenic
purpura; arterial insufficiency, usually of the Raynaud
type.<br/>Central Nervous
System: 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.<br/>Gastrointestinal: Nausea,
vomiting, epigastric distress, abdominal cramping, diarrhea,
constipation, mesenteric arterial thrombosis, ischemic
colitis.<br/>Allergic: Pharyngitis
and agranulocytosis; erythematous rash, fever combined with
aching and sore throat; laryngospasm, and respiratory
distress.<br/>Respiratory: Bronchospasm.<br/>Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic
purpura.<br/>Autoimmune: In
extremely rare instances, systemic lupus erythematosus has been
reported.<br/>Miscellaneous: 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.
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Cardiac Failure: 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.<br/>Nonallergic
Bronchospasm (e.g., Chronic Bronchitis, Emphysema): 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.<br/>Major Surgery: 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.<br/>Diabetes and
Hypoglycemia: 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.<br/>Thyrotoxicosis: 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 Tand reverse T, and
decreasing T.<br/>Wolff-Parkinson-White Syndrome: 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.
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Cardiac Arrhythmias: Intravenous
administration is usually reserved for life-threatening
arrhythmias or those occurring under anesthesia.
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Propranolol Hydrochloride
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