Ischemic Heart Disease Following abrupt cessation of therapy
with certain beta-blocking agents, exacerbations of angina
pectoris and, in some cases, myocardial infarction have occurred.
When discontinuing chronically administered metoprolol,
particularly in patients with ischemic heart disease, the dosage
should be gradually reduced over a period of 1 to 2 weeks and the
patient should be carefully monitored. If angina markedly worsens
or acute coronary insufficiency develops, metoprolol
administration should be reinstated promptly, at least
temporarily, and other measures appropriate for the management of
unstable angina should be taken. Patients should be warned against
interruption or discontinuation of therapy without the physician's
advice. Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue metoprolol
therapy abruptly even in patients treated only for hypertension.
|
|
Bronchospastic Diseases
|
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT
RECEIVE BETA-BLOCKERS, including metoprolol. Because of its
relative beta1 selectivity, however, metoprolol may be used with
caution in patients with bronchospastic disease who do not respond
to, or cannot tolerate, other antihypertensive treatment. Since
beta1 selectivity is not absolute, a beta2-stimulating agent
should be administered concomitantly, and the lowest possible dose
of metoprolol tartrate should be used. In these circumstances it
would be prudent initially to administer metoprolol in smaller
doses three times daily, instead of larger doses two times daily,
to avoid the higher plasma levels associated with the longer
dosing interval. (See DOSAGE AND
ADMINISTRATION.)
|
|
Major Surgery
|
The necessity or desirability of withdrawing beta-blocking
therapy, including metoprolol, prior to major surgery is
controversial; the impaired ability of the heart to respond to
reflex adrenergic stimuli may augment the risks of general
anesthesia and surgical procedures.
Metoprolol, like other
beta-blockers, 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.
Difficulty in restarting and maintaining the heartbeat has also
been reported with beta-blockers.
|
Diabetes and Hypoglycemia Metoprolol should be used
with caution in diabetic patients if a beta-blocking agent is
required. Beta-blockers may mask tachycardia occurring with
hypoglycemia, but other manifestations such as dizziness and
sweating may not be significantly affected.
Pheochromocytoma In
patients known to have, or suspected of having, a
pheochromocytoma, metoprolol is contraindicated (see
CONTRAINDIATIONS). If metoprolol is
required, it should be given in combination with an alpha
blocker, and only after the alpha blocker has been
initiated. Administration of beta-blockers alone in the
setting of pheochromocytoma have been associated with a
paradoxical increase in blood pressure due to the attenuation of
beta-mediated vasodilatation in skeletal muscle.
|
DESCRIPTION
Metoprolol tartrate, USP is a selective beta1-adrenoreceptor blocking agent, available as 25, 50 and 100 mg
tablets for oral administration. Metoprolol tartrate is
(±)-1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol (2:1) dextro-tartrate salt. Its structural formula is:
Metoprolol tartrate is a white, practically odorless, crystalline powder with a
molecular weight of 684.82. It is very soluble in water; freely soluble in
methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone;
and insoluble in ether.
Each tablet for oral administration contains 25
mg, 50 mg or 100 mg of metoprolol tartrate.
The tablets contain the
following inactive ingredients: microcrystalline cellulose, corn starch, sodium
starch glycollate, colloidal silicon dioxide, sodium lauryl sulfate, talc,
magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and
polysorbate 80. In addition, 50 mg tablet contains D&C Red #30 Aluminium
Lake and 100 mg tablet contains FD&C Blue #2 Aluminium Lake as coloring
agents.
CLINICAL PHARMACOLOGY
Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal
studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This
preferential effect is not absolute, however, and at higher doses, metoprolol
also inhibits beta2 adrenoreceptors, chiefly located in
the bronchial and vascular musculature.
Clinical pharmacology studies
have confirmed the beta-blocking activity of metoprolol in man, as shown by (1)
reduction in heart rate and cardiac output at rest and upon exercise, (2)
reduction of systolic blood pressure upon exercise, (3) inhibition of
isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic
tachycardia.
Relative beta1 selectivity has been
confirmed by the following: (1) In normal subjects, metoprolol is unable to
reverse the beta2-mediated vasodilating effects of
epinephrine. This contrasts with the effect of
nonselective (beta1 plus beta2)
beta-blockers, which completely reverse the vasodilating effects of epinephrine.
(2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker,
propranolol, at equivalent beta1-receptor blocking
doses.
Metoprolol has no intrinsic sympathomimetic activity, and
membrane-stabilizing activity is detectable only at doses much greater than
required for beta-blockade. Metoprolol crosses the blood-brain barrier and has
been reported in the CSF in a concentration 78% of the simultaneous plasma
concentration. Animal and human experiments indicate that metoprolol slows the
sinus rate and decreases AV nodal conduction.
In controlled clinical
studies, metoprolol tartrate has been shown to be an effective antihypertensive
agent when used alone or as concomitant therapy with thiazide-type diuretics, at
dosages of 100 to 450 mg daily. In controlled, comparative, clinical studies,
metoprolol has been shown to be as effective an antihypertensive agent as
propranolol, methyldopa, and thiazide-type diuretics, and to be equally
effective in supine and standing positions.
The mechanism of the
antihypertensive effects of beta-blocking agents has not been
elucidated. However, several possible mechanisms have been proposed: (1)
competitive antagonism of catecholamines at peripheral (especially cardiac)
adrenergic neuron sites, leading to decreased cardiac output; (2) a central
effect leading to reduced sympathetic outflow to the periphery; and (3)
suppression of renin activity.
By blocking catecholamine-induced
increases in heart rate, in velocity and extent of myocardial contraction, and
in blood pressure, metoprolol reduces the oxygen requirements of the heart at
any given level of effort, thus making it useful in the long-term management of
angina pectoris. However, in patients with heart failure, beta-adrenergic
blockade may increase oxygen requirements by increasing left ventricular fiber
length and end-diastolic pressure.
Although beta-adrenergic receptor
blockade is useful in the treatment of angina and hypertension, there are
situations in which sympathetic stimulation is vital. In patients with severely
damaged hearts, adequate ventricular function may depend on sympathetic drive.
In the presence of AV block, beta-blockade may prevent the necessary
facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction
by interfering with endogenous adrenergic bronchodilator activity in patients
subject to bronchospasm and may also interfere with exogenous bronchodilators in
such patients.
In controlled clinical trials, metoprolol tartrate,
administered two or four times daily, has been shown to be an effective
antianginal agent, reducing the number of angina attacks and increasing exercise
tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. A
controlled, comparative, clinical trial showed that metoprolol was
indistinguishable from propranolol in the treatment of angina
pectoris.
In a large (1,395 patients randomized), double-blind,
placebo-controlled clinical study, metoprolol was shown to reduce 3-month
mortality by 36% in patients with suspected or definite myocardial
infarction.
Patients were randomized and treated as soon as possible
after their arrival in the hospital, once their clinical condition had
stabilized and their hemodynamic status had been carefully evaluated. Subjects
were ineligible if they had hypotension, bradycardia, peripheral signs of shock,
and/or more than minimal basal rales as signs of congestive heart failure.
Initial treatment consisted of intravenous followed by oral administration of
metoprolol tartrate or placebo, given in a coronary care or comparable unit.
Oral maintenance therapy with metoprolol or placebo was then continued for 3
months. After this double-blind period, all patients were given metoprolol and
followed up to 1 year.
The median delay from the onset of symptoms to the
initiation of therapy was 8 hours in both the metoprolol and placebo treatment
groups. Among patients treated with metoprolol, there were comparable reductions
in 3-month mortality for those treated early (≤ 8 hours) and those in whom
treatment was started later. Significant reductions in the incidence of
ventricular fibrillation and in chest pain following initial intravenous therapy
were also observed with metoprolol and were independent of the interval, between
onset of symptoms and initiation of therapy.
The precise mechanism of
action of metoprolol in patients with suspected or definite myocardial
infarction is not known.
In this study, patients treated with metoprolol
received the drug both very early (intravenously) and during a subsequent
3-month period, while placebo patients received no beta-blocker treatment for
this period. The study thus was able to show a benefit from the overall
metoprolol regimen but cannot separate the benefit of very early intravenous
treatment from the benefit of later beta-blocker therapy. Nonetheless, because
the overall regimen showed a clear beneficial effect on survival without
evidence of an early adverse effect on survival, one acceptable dosage regimen
is the precise regimen used in the trial. Because the specific benefit of very
early treatment remains to be defined however, it is also reasonable to
administer the drug orally to patients at a later time as is recommended for
certain other beta-blockers.
Pharmacokinetics
In man, absorption of
metoprolol is rapid and complete. Plasma levels following oral administration,
however, approximate 50% of levels following intravenous administration,
indicating about 50% first-pass metabolism.
Plasma levels achieved are
highly variable after oral administration. Only a small fraction of the drug
(about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of
R- and S-enantiomers. Less than 5% of an oral dose of metoprolol is recovered
unchanged in the urine; the rest is excreted by the kidneys as metabolites that
appear to have no clinical significance. The systemic availability and half-life
of metoprolol in patients with renal failure do not differ to a clinically
significant degree from those in normal subjects. Consequently, no reduction in
dosage is usually needed in patients with chronic renal
failure.
Metoprolol is extensively metabolized by the cytochrome P450
enzyme system in the liver. The oxidative metabolism of metoprolol is under
genetic control with a major contribution of the polymorphic cytochrome P450
isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of
the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less
than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit
several-fold higher plasma concentrations of metoprolol than extensive
metabolizers with normal CYP2D6 activity. The elimination half-life of
metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive
metabolizers. However, the CYP2D6 dependent metabolism of metoprolol seems to
have little or no effect on safety or tolerability of the drug. None of the
metabolites of metoprolol contribute significantly to its beta-blocking
effect.
Significant beta-blocking effect (as measured by reduction of
exercise heart rate) occurs within 1 hour after oral administration, and its
duration is dose-related. For example, a 50% reduction of the maximum registered
effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5, and 6.4
hours, respectively, in normal subjects. After repeated oral dosages of 100 mg
twice daily, a significant reduction in exercise systolic blood pressure was
evident at 12 hours.
Following intravenous administration of metoprolol,
the urinary recovery of unchanged drug is approximately 10%. When the drug was
infused over a 10-minute period, in normal volunteers, maximum beta-blockade was
achieved at approximately 20 minutes. Doses of 5 mg and 15 mg yielded a maximal
reduction in exercise-induced heart rate of approximately 10% and 15%,
respectively. The effect on exercise heart rate decreased linearly with time at
the same rate for both doses, and disappeared at approximately 5 hours and 8
hours for the 5 mg and 15 mg doses, respectively.
Equivalent maximal
beta-blocking effect is achieved with oral and intravenous doses in the ratio of
approximately 2.5:1.
There is a linear relationship between the log of
plasma levels and reduction of exercise heart rate. However, antihypertensive
activity does not appear to be related to plasma levels. Because of variable
plasma levels attained with a given dose and lack of a consistent relationship
of antihypertensive activity to dose, selection of proper dosage requires
individual titration.
In several studies of patients with acute
myocardial infarction, intravenous followed by oral administration of metoprolol
caused a reduction in heart rate, systolic blood pressure, and cardiac output.
Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic
pressure remained unchanged.
In patients with angina pectoris, plasma
concentration measured at 1 hour is linearly related to the oral dose within the
range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are
reduced in relation to the logarithm of the oral dose of metoprolol. The
increase in exercise capacity and the reduction in left ventricular ischemia are
also significantly related to the logarithm of the oral dose.
In elderly
subjects with clinically normal renal and hepatic function, there are no
significant differences in metoprolol pharmacokinetics compared to young
subjects.
INDICATIONS AND USAGE
Hypertension
Metoprolol tartrate tablets are
indicated for the treatment of hypertension. They may be used alone or in
combination with other antihypertensive agents.
Angina Pectoris
Metoprolol tartrate tablets
are indicated in the long-term treatment of angina pectoris.
Myocardial Infarction
Metoprolol tartrate
tablets are indicated in the treatment of hemodynamically stable patients with
definite or suspected acute myocardial infarction to reduce cardiovascular
mortality. Treatment with intravenous metoprolol can be initiated as soon as the
patient's clinical condition allows (see
DOSAGE AND
ADMINISTRATION,
CONTRAINDICATIONS, and
WARNINGS). Alternatively, treatment can begin within 3 to
10 days of the acute event (see
DOSAGE AND
ADMINISTRATION).
CONTRAINDICATIONS
Hypertension and Angina
Metoprolol tartrate
tablets are contraindicated in sinus bradycardia, heart block greater than first
degree, cardiogenic shock, and overt cardiac failure (see
WARNINGS).
Hypersensitvity to metoprolol and
related derivatives, or to any of the excipients; hypersensitivity to other
beta-blockers (cross sensitivity between beta-blockers can
occur).
Sick-sinus syndrome.
Severe peripheral arterial
circulatory disorders.
Pheochromocytoma (see
WARNINGS).
Myocardial Infarction
Metoprolol tartrate
tablets are contraindicated in patients with a heart rate less than 45 beats/min;
second- and third-degree heart block; significant first-degree heart block (P-R
interval greater than or equal to 0.24 sec); systolic blood pressure less than 100 mmHg; or
moderate-to-severe cardiac failure (see
WARNINGS).
WARNINGS
Hypertension and Angina
Cardiac Failure
Sympathetic stimulation is a
vital component supporting circulatory function in congestive heart failure, and
beta-blockade carries the potential hazard of further depressing myocardial
contractility and precipitating more severe failure. In hypertensive and angina
patients who have congestive heart failure controlled by digitalis and
diuretics, metoprolol should be administered cautiously.
In Patients Without a History of Cardiac
Failure
Continued depression of the myocardium with beta-blocking agents
over a period of time can, in some cases, lead to cardiac failure. At the first
sign or symptom of impending cardiac failure, patients should be fully
digitalized and/or given a diuretic. The response should be observed closely. If
cardiac failure continues, despite adequate digitalization and diuretic therapy,
metoprolol should be withdrawn.
Ischemic Heart Disease
Following abrupt
cessation of therapy with certain beta-blocking agents, exacerbations of angina
pectoris and, in some cases, myocardial infarction have occurred. When
discontinuing chronically administered metoprolol, particularly in patients with
ischemic heart disease, the dosage should be gradually reduced over a period of
1 to 2 weeks and the patient should be carefully monitored. If angina markedly
worsens or acute coronary insufficiency develops, metoprolol administration
should be reinstated promptly, at least temporarily, and other measures
appropriate for the management of unstable angina should be taken. Patients
should be warned against interruption or discontinuation of therapy without the
physician's advice. Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly
even in patients treated only for hypertension.Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE
BETA-BLOCKERS, including metoprolol. Because of its relative beta1 selectivity, however, metoprolol may be used with caution in
patients with bronchospastic disease who do not respond to, or cannot tolerate,
other antihypertensive treatment. Since beta1 selectivity
is not absolute, a beta2-stimulating agent should be
administered concomitantly, and the lowest possible dose of metoprolol tartrate
should be used. In these circumstances it would be prudent initially to
administer metoprolol in smaller doses three times daily, instead of larger
doses two times daily, to avoid the higher plasma levels associated with the
longer dosing interval. (See DOSAGE AND
ADMINISTRATION.)Major Surgery
The necessity
or desirability of withdrawing beta-blocking therapy, including metoprolol,
prior to major surgery is controversial; the impaired ability of the heart to
respond to reflex adrenergic stimuli may augment the risks of general anesthesia
and surgical procedures.
Metoprolol, like other beta-blockers, 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. Difficulty in
restarting and maintaining the heartbeat has also been reported with
beta-blockers.Diabetes and Hypoglycemia
Metoprolol should be used with caution in diabetic patients if a
beta-blocking agent is required. Beta-blockers may mask tachycardia occurring
with hypoglycemia, but other manifestations such as dizziness and sweating may
not be significantly affected.Pheochromocytoma
In patients
known to have, or suspected of having, a pheochromocytoma, metoprolol is
contraindicated (see CONTRAINDIATIONS). If metoprolol
is required, it should be given in combination with an alpha blocker, and only
after the alpha blocker has been initiated. Administration of beta-blockers
alone in the setting of pheochromocytoma have been associated with a paradoxical
increase in blood pressure due to the attenuation of beta-mediated
vasodilatation in skeletal muscle.Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g.,
tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis
should be managed carefully to avoid abrupt withdrawal of beta-blockade, which
might precipitate a thyroid storm.Myocardial Infarction
Cardiac Failure
Sympathetic stimulation is
a vital component supporting circulatory function, and beta-blockade carries the
potential hazard of depressing myocardial contractility and precipitating or
exacerbating minimal cardiac failure.
During treatment with metoprolol,
the hemodynamic status of the patient should be carefully monitored. If heart
failure occurs or persists despite appropriate treatment, metoprolol should be
discontinued.
Bradycardia
Metoprolol produces a decrease in
sinus heart rate in most patients; this decrease is greatest among patients with
high initial heart rates and least among patients with low initial heart rates.
Acute myocardial infarction (particularly inferior infarction) may in itself
produce significant lowering of the sinus rate. If the sinus rate decreases to
less than 40 beats/min, particularly if associated with evidence of lowered cardiac
output, atropine (0.25 to 0.5 mg) should be administered intravenously. If
treatment with atropine is not successful, metoprolol should be discontinued,
and cautious administration of isoproterenol or installation of a cardiac
pacemaker should be considered.
AV Block
Metoprolol slows AV conduction and
may produce significant first-(P-R interval greater than or equal to 0.26 sec), second-, or
third-degree heart block. Acute myocardial infarction also produces heart
block.
If heart block occurs, metoprolol should be discontinued and
atropine (0.25 to 0.5 mg) should be administered intravenously. If treatment
with atropine is not successful, cautious administration of isoproterenol or
installation of a cardiac pacemaker should be considered.
Hypotension
If hypotension (systolic blood
pressure less than or equal to 90 mmHg) occurs, metoprolol should be discontinued, and the
hemodynamic status of the patient and the extent of myocardial damage carefully
assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and
arterial pressures may be required. Appropriate therapy with fluids, positive
inotropic agents, balloon counterpulsation, or other treatment modalities should
be instituted. If hypotension is associated with sinus bradycardia or AV block,
treatment should be directed at reversing these (see above).
Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE
BETA-BLOCKERS, including metoprolol. Because of its relative beta1 selectivity, metoprolol may be used with extreme caution in
patients with bronchospastic disease. Because it is unknown to what extent
beta2-stimulating agents may exacerbate myocardial
ischemia and the extent of infarction, these agents should not be used prophylactically. If bronchospasm not related
to congestive heart failure occurs, metoprolol should be discontinued. A
theophylline derivative or a beta2 agonist may be
administered cautiously, depending on the clinical condition of the patient.
Both theophylline derivatives and beta2 agonists may
produce serious cardiac arrhythmias.
PRECAUTIONS
General
Metoprolol should be used with
caution in patients with impaired hepatic function.
Information for Patients
Patients should be
advised to take metoprolol regularly and continuously, as directed, with or
immediately following meals. If a dose should be missed, the patient should take
only the next scheduled dose (without doubling it). Patients should not
discontinue metoprolol without consulting the physician.
Patients should
be advised (1) to avoid operating automobiles and machinery or engaging in other
tasks requiring alertness until the patient’s response to therapy with
metoprolol has been determined; (2) to contact the physician if any difficulty
in breathing occurs; (3) to inform the physician or dentist before any type of
surgery that he or she is taking metoprolol.
Drug Interactions
Catecholamine-depleting
drugs (e.g., reserpine) may have an additive effect when given with
beta-blocking agents. Patients treated with metoprolol plus a catecholamine
depletor should therefore be closely observed for evidence of hypotension or
marked bradycardia, which may produce vertigo, syncope, or postural
hypotension.
Both digitalis glycosides and beta-blockers slow
atrioventricular conduction and decrease heart rate. Concomitant use can
increase the risk of bradycardia.
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.
General Anesthetics
Some inhalation
anesthetics may enhance the cardiodepressant effect of beta-blockers (see
WARNINGS, Major Surgery).
CYP2D6 Inhibitors
Potent inhibitors of the
CYP2D6 enzyme may increase the plasma concentration of metoprolol. Strong
inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer
(see Pharmacokinetics section). Caution should therefore be exercised when
co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically
significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine,
paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics
such as quinidine or propafenone, antiretrovirals such as ritonavir,
antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine
or quinidine, antifungals such as terbinafine and medications for stomach ulcers
such as cimetidine.
Clonidine
If a patient is treated with
clonidine and metoprolol concurrently, and clonidine treatment is to be
discontinued, metoprolol should be stopped several days before clonidine is
withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be
increased in patients receiving concurrent beta-blocker treatment.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Long-term studies in animals have been conducted to evaluate
carcinogenic potential. In a 2-year study in rats at three oral dosage levels of
up to 800 mg/kg per day, there was no increase in the development of
spontaneously occurring benign or malignant neoplasms of any type. The only
histologic changes that appeared to be drug related were an increased incidence
of generally mild focal accumulation of foamy macrophages in pulmonary alveoli
and a slight increase in biliary hyperplasia. In a 21-month study in Swiss
albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung
tumors (small adenomas) occurred more frequently in female mice receiving the
highest dose than in untreated control animals. There was no increase in
malignant or total (benign plus malignant) lung tumors, or in the overall
incidence of tumors or malignant tumors. This 21-month study was repeated in
CD-1 mice, and no statistically or biologically significant differences were
observed between treated and control mice of either sex for any type of
tumor.
All mutagenicity tests performed (a dominant lethal study in
mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome
mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were
negative.
No evidence of impaired fertility due to metoprolol was
observed in a study performed in rats at doses up to 55.5 times the maximum
daily human dose of 450 mg.
Pregnancy Category C
Metoprolol has been
shown to increase postimplantation loss and decrease neonatal survival in rats
at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution
studies in mice confirm exposure of the fetus when metoprolol is administered to
the pregnant animal. These studies have revealed no evidence of impaired
fertility or teratogenicity. There are no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly
needed.
Nursing Mothers
Metoprolol is excreted in
breast milk in a very small quantity. An infant consuming 1 liter of breast milk
daily would receive a dose of less than 1 mg of the drug. Caution should be
exercised when metoprolol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in
pediatric patients have not been established.
Geriatric Use
Clinical trials of metoprolol
in hypertension did not include sufficient numbers of elderly patients to
determine whether patients over 65 years of age differ from younger subjects in
their response to metoprolol. Other reported clinical experience in elderly
hypertensive patients has not identified any difference in response from younger
patients.
In worldwide clinical trials of metoprolol in myocardial
infarction, where approximately 478 patients were over 65 years of age (0 over
75 years of age), no age-related differences in safety and effectiveness were
found. Other reported clinical experience in myocardial infarction has not
identified differences in response between the elderly and younger patients.
However, greater sensitivity of some elderly individuals taking metoprolol
cannot be categorically ruled out. Therefore, in general, it is recommended that
dosing proceed with caution in this population.
ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects
have been mild and transient.
Central Nervous System: Tiredness and dizziness have
occurred in about 10 of 100 patients. Depression has been reported in about 5 of
100 patients. Mental confusion and short-term memory loss have been reported.
Headache, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath
and bradycardia have occurred in approximately 3 of 100 patients. Cold
extremities; arterial insufficiency, usually of the Raynaud type; palpitations;
congestive heart failure; peripheral edema; and hypotension have been reported
in about 1 of 100 patients. Gangrene in patients with pre-existing severe
peripheral circulatory disorders has also been reported very rarely. (See
CONTRAINDICATIONS,
WARNINGS, and
PRECAUTIONS.)
Respiratory: Wheezing (bronchospasm) and dyspnea
have been reported in about 1 of 100 patients (see
WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has
occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain,
constipation, flatulence, and heartburn have been reported in about 1 of 100
patients. Vomiting was a common occurrence. Postmarketing experience reveals
very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction.
Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase
elevations have also been reported.
Hypersensitive Reactions: Pruritus or rash have
occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening
of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported
in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, and
tinnitus have also been reported.
There have been rare reports of
reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug
should be considered if any such reaction is not otherwise explicable. There
have been very rare reports of weight gain, arthritis, and retroperitoneal
fibrosis (relationship to metoprolol has not been definitely
established).
The oculomucocutaneous syndrome associated with the
beta-blocker practolol has not been reported with metoprolol.
Myocardial Infarction
Central Nervous System: Tiredness has been reported
in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations,
headache, dizziness, visual disturbances, confusion, and reduced libido have
also been reported, but a drug relationship is not clear.
Cardiovascular: In the randomized
comparison of metoprolol and placebo described in the
CLINICAL PHARMACOLOGY section, the following adverse
reactions were reported:
| Metoprolol
| Placebo
|
Hypotension (systolic BP less than 90 mm Hg)
| 27.4%
| 23.2%
|
Bradycardia (heart rate less than 40
beats/min)
| 15.9%
| 6.7%
|
Second- or third-degree heart block
| 4.7%
| 4.7%
|
First-degree heart block (P-R greater than or equal to 0.26
sec)
| 5.3%
| 1.9%
|
Heart failure
| 27.5%
| 29.6%
|
Respiratory: Dyspnea of pulmonary origin has been
reported in fewer than 1 of 100 patients.
Gastrointestinal: Nausea and abdominal pain have
been reported in fewer than 1 of 100 patients.
Dermatologic: Rash and worsened psoriasis have been
reported, but a drug relationship is not clear.
Miscellaneous: Unstable diabetes and claudication
have been reported, but a drug relationship is not clear.
Potential Adverse Reactions
A variety of
adverse reactions not listed above have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse reactions to
metoprolol.
Central Nervous System:
Reversible mental depression progressing to catatonia; 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.
Cardiovascular: Intensification of AV block (see
CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic
purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching
and sore throat, laryngospasm, and respiratory distress.
Postmarketing Experience
The following adverse
reactions have been reported during postapproval use of metoprolol: confusional
state, an increase in blood triglycerides and a decrease in High Density
Lipoprotein (HDL). Because these reports are from a population of uncertain size
and are subject to confounding factors, it is not possible to reliably estimate
their frequency.
OVERDOSAGE
Acute Toxicity: Several cases of overdosage have been
reported, some leading to death.
Oral LD50’s
(mg/kg): mice, 1158 to 2460; rats, 3090 to 4670.
Signs and Symptoms
Potential signs and
symptoms associated with overdosage with metoprolol are bradycardia,
hypotension, bronchospasm, and cardiac failure.
Treatment
There is no specific
antidote.
In general, patients with acute or recent myocardial infarction
may be more hemodynamically unstable than other patients and should be treated
accordingly (see
WARNINGS: Myocardial
Infarction).
On the basis of the pharmacologic actions of
metoprolol, the following general measures should be employed:
Elimination of the Drug:
Gastric lavage should be performed.
Bradycardia:Atropine should be
administered. If there is no response to vagal blockade, isoproterenol should be
administered cautiously.
Hypotension: A vasopressor should be administered, e.g.,
levarterenol or dopamine.
Bronchospasm:A beta
2-stimulating
agent and/or a theophylline derivative should be administered.
Cardiac Failure: A digitalis
glycoside and diuretic should be administered. In shock resulting from
inadequate cardiac contractility, administration of dobutamine, isoproterenol,
or glucagon may be considered.
DOSAGE AND ADMINISTRATION
Hypertension
The dosage of metoprolol
tartrate tablets should be individualized. Metoprolol tartrate tablets should be
taken with or immediately following meals.
The usual initial dosage is
100 mg daily in single or divided doses, whether used alone or added to a
diuretic. The dosage may be increased at weekly (or longer) intervals until
optimum blood pressure reduction is achieved. In general, the maximum effect of
any given dosage level will be apparent after 1 week of therapy. The effective
dosage range is 100 to 450 mg per day. Dosages above 450 mg per day have not
been studied. While once-daily dosing is effective and can maintain a reduction
in blood pressure throughout the day, lower doses (especially 100 mg) may not
maintain a full effect at the end of the 24-hour period, and larger or more
frequent daily doses may be required. This can be evaluated by measuring blood
pressure near the end of the dosing interval to determine whether satisfactory
control is being maintained throughout the day. Beta
1
selectivity diminishes as the dose of metoprolol is increased.
Angina Pectoris
The dosage of metoprolol
tartrate tablets should be individualized. Metoprolol tartrate tablets should be
taken with or immediately following meals.
The usual initial dosage is
100 mg daily, given in two divided doses. The dosage may be gradually increased
at weekly intervals until optimum clinical response has been obtained or there
is pronounced slowing of the heart rate. The effective dosage range is 100 to
400 mg per day. Dosages above 400 mg per day have not been studied. If treatment
is to be discontinued, the dosage should be reduced gradually over a period of 1
to 2 weeks. (See
WARNINGS.)
Myocardial Infarction
Early Treatment
During the early phase of
definite or suspected acute myocardial infarction, treatment with metoprolol
tartrate tablets can be initiated as soon as possible after the patient's
arrival in the hospital. Such treatment should be initiated in a coronary care
or similar unit immediately after the patient’s hemodynamic condition has
stabilized.
Treatment in this early phase should begin with the
intravenous administration of three bolus injections of 5 mg of metoprolol
tartrate each; the injections should be given at approximately 2-minute
intervals. During the intravenous administration of metoprolol, blood pressure,
heart rate, and electrocardiogram should be carefully monitored.
In
patients who tolerate the full intravenous dose (15 mg), metoprolol tartrate
tablets, 50 mg every 6 hours, should be initiated 15 minutes after the last
intravenous dose and continued for 48 hours. Thereafter, patients should receive
a maintenance dosage of 100 mg twice daily (see
Late
Treatment below).
Patients who appear not to tolerate the full
intravenous dose should be started on metoprolol tartrate tablets either 25 mg
or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after
the last intravenous dose or as soon as their clinical condition allows. In
patients with severe intolerance, treatment with metoprolol should be
discontinued (see
WARNINGS).
Late Treatment
Patients with
contraindications to treatment during the early phase of suspected or definite
myocardial infarction, patients who appear not to tolerate the full early
treatment, and patients in whom the physician wishes to delay therapy for any
other reason should be started on metoprolol tartrate tablets, 100 mg twice
daily, as soon as their clinical condition allows. Therapy should be continued
for at least 3 months. Although the efficacy of metoprolol beyond 3 months has
not been conclusively established, data from studies with other beta-blockers
suggest that treatment should be continued for 1 to 3 years.
HOW SUPPLIED
Metoprolol Tartrate Tablets, USP are available as follows:
Tablets 25 mg are white round shaped, film
coated tablets debossed with ‘C over 73’ on one side and deep break line on
other side.
Bottles of 30
| NDC 54868-5021-0
|
Bottles of 60
| NDC 54868-5021-1
|
Bottles of 90
| NDC 54868-5021-3
|
Bottles of 100
| NDC 54868-5021-2
|
Bottles of 120
| NDC 54868-5021-5
|
Bottles of 180
| NDC 54868-5021-4
|
Tablets 50
mg are pink round shaped, film coated tablets debossed with ‘C
over 74’ on one side and deep break line on other
side.
Bottles of 10
| NDC 54868-2989-4
|
Bottles of 15
| NDC 54868-2989-6
|
Bottles of 30
| NDC 54868-2989-2
|
Bottles of 60
| NDC 54868-2989-3
|
Bottles of 90
| NDC 54868-2989-5
|
Bottles of 100
| NDC 54868-2989-0
|
Bottles of 180
| NDC 54868-2989-7
|
Tablets
100 mg are light blue round shaped, film coated tablets debossed
with ‘C over 75’ on one side and deep break line on other
side.
Bottles of 30
| NDC 54868-2990-0
|
Bottles of 45
| NDC 54868-2990-4
|
Bottles of 60
| NDC 54868-2990-3
|
Bottles of 100
| NDC 54868-2990-2
|
Bottles of 180
| NDC 54868-2990-5
|
Store at 20° to 25°C (68° to
77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].
Protect from
moisture.
Dispense in a tight,
light-resistant container as defined in the USP using a child-resistant
closure.
Manufactured for:
Aurobindo Pharma USA,
Inc.
2400 Route 130 North
Dayton, NJ 08810
Manufactured
by:
Aurobindo Pharma Limited
Hyderabad-500 072,
India
Revised: 01/2009
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK 74146
PRINCIPAL DISPLAY PANEL
Metoprolol Tartrate Tablets, USP
25 mg
50 mg
100 mg
Physicians Total Care, Inc.