Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1066
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Flumazenil (Injection, Solution)
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Flumazenil
injection is recommended for intravenous use only. It is compatible with
5% dextrose in water, lactated Ringer's and 0.9% sodium
chloride solutions. If flumazenil injection is drawn into a syringe or
mixed with any of these solutions, it should be discarded after 24
hours. For optimum sterility, flumazenil injection should remain in the
vial until just before use. As with all parenteral drug products,
flumazenil injection should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and
container permit. To minimize the
likelihood of pain at the injection site, flumazenil injection should be
administered through a freely running intravenous infusion into a large
vein.<br/>Reversal of
Conscious Sedation:<br/>Adult
Patients: For
the reversal of the sedative effects of benzodiazepines
administered for conscious sedation, the recommended
initial dose of flumazenil injection is 0.2 mg (2 mL)
administered intravenously over 15 seconds. If the
desired level of consciousness is not obtained after
waiting an additional 45 seconds, a second dose of 0.2
mg (2 mL) can be injected and repeated at 60-second
intervals where necessary (up to a maximum of 4
additional times) to a maximum total dose of 1 mg (10
mL). The dosage should be individualized based on the
patient's response, with most patients
responding to doses of 0.6 mg to 1 mg . In
the event of resedation, repeated doses may be
administered at 20-minute intervals as needed. For
repeat treatment, no more than 1 mg (given as 0.2
mg/min) should be administered at any one time, and no
more than 3 mg should be given in any one hour. It
is recommended that flumazenil injection be administered
as the series of small injections described (not as a
single bolus injection) to allow the practitioner to
control the reversal of sedation to the approximate
endpoint desired and to minimize the possibility of
adverse effects (see INDIVIDUALIZATION OF
DOSAGE).<br/>Pediatric
Patients: For
the reversal of the sedative effects of benzodiazepines
administered for conscious sedation in pediatric
patients greater than 1 year of age, the recommended
initial dose is 0.01 mg/kg (up to 0.2 mg) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an
additional 45 seconds, further injections of 0.01 mg/kg
(up to 0.2 mg) can be administered and repeated at
60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 0.05
mg/kg or 1 mg, whichever is lower. The dose should be
individualized based on the patient's response.
The mean total dose administered in the pediatric
clinical trial of flumazenil was 0.65 mg (range: 0.08 mg
to 1 mg). Approximately one-half of patients required
the maximum of five injections. Resedation occurred in 7 of 60 pediatric patients who
were fully alert 10 minutes after the start of
flumazenil injection administration . The safety
and efficacy of repeated flumazenil administration in
pediatric patients experiencing resedation have not been
established. It
is recommended that flumazenil injection be administered
as the series of small injections described (not as a
single bolus injection) to allow the practitioner to
control the reversal of sedation to the approximate
endpoint desired and to minimize the possibility of
adverse effects . The
safety and efficacy of flumazenil injection in the
reversal of conscious sedation in pediatric patients
below the age of 1 year have not been
established.<br/>Reversal of General
Anesthesia in Adult Patients: For the
reversal of the sedative effects of benzodiazepines administered
for general anesthesia, the recommended initial dose of
flumazenil injection is 0.2 mg (2 mL) administered intravenously
over 15 seconds. If the desired level of consciousness is not
obtained after waiting an additional 45 seconds, a second dose
of 0.2 mg (2 mL) can be injected and repeated at 60-second
intervals where necessary (up to a maximum of 4 additional
times) to a maximum total dose of 1 mg (10 mL). The dosage
should be individualized based on thepatient's
response, with most patients responding to doses of 0.6 mg to 1
mg . In the
event of resedation, repeated doses may be administered at
20-minute intervals as needed. For repeat treatment, no more
than 1 mg (given as 0.2 mg/min) should be administered at any
one time, and no more than 3 mg should be given in any one hour. It is
recommended that flumazenil injection be administered as the
series of small injections described (not as a single bolus
injection) to allow the practitioner to control the reversal of
sedation to the approximate endpoint desired and to minimize the
possibility of adverse effects .<br/>Management of
Suspected Benzodiazepine Overdose in Adult Patients: For initial
management of a known or suspected benzodiazepine overdose, the
recommended initial dose of flumazenil injection is 0.2 mg (2
mL) administered intravenously over 30 seconds. If the desired
level of consciousness is not obtained after waiting 30 seconds,
a further dose of 0.3 mg (3 mL) can be administered over another
30 seconds. Further doses of 0.5 mg (5 mL) can be administered
over 30 seconds at 1-minute intervals up to a cumulative dose of
3 mg. Do not rush
the administration of flumazenil injection. Patients should have
a secure airway and intravenous access before administration of
the drug and be awakened gradually . Most
patients with a benzodiazepine overdose will respond to a
cumulative dose of 1 mg to 3 mg of flumazenil injection, and
doses beyond 3 mg do not reliably produce additional effects. On
rare occasions, patients with a partial response at 3 mg may
require additional titration up to a total dose of 5 mg
(administered slowly in the same manner). If a
patient has not responded 5 minutes after receiving a cumulative
dose of 5 mg of flumazenil injection, the major cause of
sedation is likely not to be due to benzodiazepines, and
additional flumazenil injection is likely to have no effect. In the
event of resedation, repeated doses may be given at 20-minute
intervals if needed. For repeat treatment, no more than 1 mg
(given as 0.5 mg/min) should be given at any one time and no
more than 3 mg should be given in any one hour.<br/>Safety and Handling: Flumazenil
injection is supplied in sealed dosage forms and poses no known
risk to the healthcare provider. Routine care should be taken to
avoid aerosol generation when preparing syringes for injection,
and spilled medication should be rinsed from the skin with cool
water.<br/>HOW SUPPLIED: 5 mL
Multiple-dose vials containing 0.1 mg/mL flumazenil--boxes of 10
(NDC 10019-321-01) 10 mL
Multiple-dose vials containing 0.1 mg/mL flumazenil--boxes of 10
(NDC 10019-321-02)<br/>Storage: Store at 20��-25��C (68��-77��F), excursions permitted to
15��-30��C (59��-86��F)
[see USP Controlled Room Temperature
]. Baxter is a
registered trademark of Baxter International Inc. Manufactured by Baxter Healthcare
Corporation Deerfield,
IL 60015 USA For Product
Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00095/4.0
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Flumazenil
injection is a benzodiazepine receptor antagonist. Chemically,
flumazenil is ethyl
8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4)benzodiazepine-3-carboxylate.
Flumazenil has an imidazobenzodiazepine structure and a calculated
molecular weight of 303.29 and the following structural
formula: Flumazenil is a
white to off-white crystalline compound with an octanol:buffer partition
coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly
soluble in acidic aqueous solutions. Flumazenil injection is available
as a sterile parenteral dosage form for intravenous administration. Each
mL contains 0.1 mg of flumazenil compounded with 1.8 mg of
methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01%
edetate disodium, and 0.01% acetic acid; the pH is adjusted to 3.5���4.5 with hydrochloric acid and/or, if necessary, sodium
hydroxide.
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Flumazenil, an
imidazobenzodiazepine derivative, antagonizes the actions of
benzodiazepines on the central nervous system. Flumazenil competitively
inhibits the activity at the benzodiazepine recognition site on the
GABA/benzodiazepine receptor complex. Flumazenil is a weak partial
agonist in some animal models of activity, but has little or no agonist
activity in man. Flumazenil does not
antagonize the central nervous system effects of drugs affecting
GABA-ergic neurons by means other than the benzodiazepine receptor
(including ethanol, barbiturates, or general anesthetics) and does not
reverse the effects of opioids. In animals
pretreated with high doses of benzodiazepines over several weeks,
flumazenil injection elicited symptoms of benzodiazepine withdrawal,
including seizures. A similar effect was seen in adult human
subjects.<br/>Pharmacodynamics: Intravenous
flumazenil has been shown to antagonize sedation, impairment of
recall, psychomotor impairment and ventilatory depression
produced by benzodiazepines in healthy human volunteers. The
duration and degree of reversal of sedative benzodiazepine
effects are related to the dose and plasma concentrations of
flumazenil as shown in the following data from a study in normal
volunteers. Generally,
doses of approximately 0.1 mg to 0.2 mg (corresponding to peak
plasma levels of 3 to 6 ng/mL) produce partial antagonism,
whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to
28 ng/mL) usually produce complete antagonism in patients who
have received the usual sedating doses of benzodiazepines. The
onset of reversal is usually evident within 1 to 2 minutes after
the injection is completed. Eighty percent response will be
reached within 3 minutes, with the peak effect occurringat 6 to
10 minutes. The duration and degree of reversal are related to
the plasma concentration of the sedating benzodiazepine as well
as the dose of flumazenil injection given. In healthy
volunteers, flumazenil injection did not alter intraocular
pressure when given alone and reversed the decrease in
intraocular pressure seen after administration of
midazolam.<br/>Pharmacokinetics: After IV
administration, plasma concentrations of flumazenil follow a
two-exponential decay model. The pharmacokinetics of flumazenil
are dose-proportional up to 100 mg.<br/>Distribution: Flumazenil is extensively distributed in the
extravascular space with an initial distribution
half-life of 4 to 11 minutes and a terminal half-life of
40 to 80 minutes. Peak concentrations of flumazenil are
proportional to dose, with an apparent initial volume of
distribution of 0.5 L/kg. The volume of distribution at
steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak
lipophilic base. Protein binding is approximately 50%
and the drug shows no preferential partitioning into red
blood cells. Albumin accounts for two thirds of plasma
protein binding.<br/>Metabolism: Flumazenil is completely (99%) metabolized. Very little
unchanged flumazenil (<1%) is found in the urine.
The major metabolites of flumazenil identified in urine
are the de-ethylated free acid and its glucuronide
conjugate. In preclinical studies there was no evidence
of pharmacologic activity exhibited by the de-ethylated
free acid.<br/>Elimination: Elimination of radiolabeled drug is essentially
complete within 72 hours, with 90% to 95% of the
radioactivity appearing in urine and 5% to 10% in the
feces. Clearance of flumazenil occurs primarily by
hepatic metabolism and is dependent on hepatic blood
flow. In pharmacokinetic studies of normal volunteers,
total clearance ranged from 0.8 to 1 L/hr/kg. Pharmacokinetic parameters following a 5-minute
infusion of a total of 1 mg of flumazenil injection mean
(coefficient of variation, range):<br/>Food
Effects: Ingestion of food during an intravenous infusion of the
drug results in a 50% increase in clearance, most likely
due to the increased hepatic blood flow that accompanies
a meal.<br/>Special
Populations:
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Flumazenil
injection is contraindicated:
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| dailymed-instance:supply |
5 mL
Multiple-dose vials containing 0.1 mg/mL flumazenil--boxes of 10
(NDC 10019-321-01) 10 mL
Multiple-dose vials containing 0.1 mg/mL flumazenil--boxes of 10
(NDC 10019-321-02)
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Return of Sedation: Flumazenil
injection may be expected to improve the alertness of patients
recovering from a procedure involving sedation or anesthesia
with benzodiazepines, but should not be substituted for an
adequate period of postprocedure monitoring. The availability of
flumazenil injection does not reduce the risks associated with
the use of large doses of benzodiazepines for sedation. Patients
should be monitored for resedation, respiratory depression (see
WARNINGS) or other persistent or recurrent agonist
effects for an adequate period of time after administration of
flumazenil injection. Resedation
is least likely in cases where flumazenil injection is
administered to reverse a low dose of a short-acting
benzodiazepine (<10 mg midazolam). It is most likely in
cases where a large single or cumulative dose of a
benzodiazepine has been given in the course of a long procedure
along with neuromuscular blocking agents and multiple anesthetic
agents. Profound
resedation was observed in 1% to 3% of adult patients in the
clinical studies. In clinical situations where resedation must
be prevented in adult patients, physicians may wish to repeat
the initial dose (up to 1 mg of flumazenil injection given at
0.2 mg/min) at 30 minutes and possibly again at 60 minutes. This
dosage schedule, although not studied in clinical trials, was
effective in preventing resedation in a pharmacologic study in
normal volunteers. The use of
flumazenil injection to reverse the effects of benzodiazepines
used for conscious sedation has been evaluated in one open-label
clinical trial involving 107 pediatric patients between the ages
of 1 and 17 years. This study suggested that pediatric patients
who have become fully awake following treatment with flumazenil
may experience a recurrence of sedation, especially younger
patients (ages 1 to 5). Resedation was experienced in 7 of 60
patients who were fully alert 10 minutes after the start of
flumazenil injection administration. No patient experienced a
return to the baseline level of sedation. Mean time to
resedation was 25 minutes (range: 19 to 50 minutes) (see
PRECAUTIONS: Pediatric Use). The safety and
effectiveness of repeated flumazenil administration in pediatric
patients experiencing resedation have not been
established.<br/>Use in the ICU: Flumazenil
injection should be used with caution in the ICU because of the
increased risk of unrecognized benzodiazepine dependence in such
settings. Flumazenil injection may produce convulsions in
patients physically dependent on benzodiazepines . Administration of flumazenil injection to diagnose
benzodiazepine-induced sedation in the ICU is not recommended
due to the risk of adverse events as described above. In
addition, the prognostic significance of a patient's
failure to respond to flumazenil in cases confounded by
metabolic disorder, traumatic injury, drugs other than
benzodiazepines, or any other reasons not associated with
benzodiazepine receptor occupancy is unknown.<br/>Use in Overdosage: Flumazenil
injection is intended as an adjunct to, not as a substitute for,
proper management of airway, assisted breathing, circulatory
access and support, internal decontamination by lavage and
charcoal, and adequate clinical evaluation. Necessary
measures should be instituted to secure airway, ventilation and
intravenous access prior to administering flumazenil. Upon
arousal, patients may attempt to withdraw endotracheal tubes
and/or intravenous lines as the result of confusion and
agitation following awakening.<br/>Head Injury: Flumazenil
injection should be used with caution in patients with head
injury as it may be capable of precipitating convulsions or
altering cerebral blood flow in patients receiving
benzodiazepines. It should be used only by practitioners
prepared to manage such complications should they
occur.<br/>Use With
Neuromuscular Blocking Agents: Flumazenil
injection should not be used until the effects of neuromuscular
blockade have been fully reversed.<br/>Use in Psychiatric
Patients: Flumazenil
injection has been reported to provoke panic attacks in patients
with a history of panic disorder.<br/>Pain on Injection: To minimize
the likelihood of pain or inflammation at the injection site,
flumazenil injection should be administered through a freely
flowing intravenous infusion into a large vein. Local irritation
may occur following extravasation into perivascular
tissues.<br/>Use in Respiratory
Disease: The primary
treatment of patients with serious lung disease who experience
serious respiratory depression due to benzodiazepines should be
appropriate ventilatory support rather than the administration of
flumazenil injection. Flumazenil is capable of partially
reversing benzodiazepine-induced alterations in ventilatory
drive in healthy volunteers, but has not been shown to be
clinically effective.<br/>Use in
Cardiovascular Disease: Flumazenil
injection did not increase the work of the heart when used to
reverse benzodiazepines in cardiac patients when given at a rate
of 0.1 mg/min in total doses of less than 0.5 mg in studies
reported in the clinical literature. Flumazenil alone had no
significant effects on cardiovascular parameters when
administered to patients with stable ischemic heart
disease.<br/>Use in Liver
Disease: The
clearance of flumazenil injection is reduced to 40% to 60% of
normal in patients with mild to moderate hepatic disease and to
25% of normal in patients with severe hepatic dysfunction (see
CLINICAL
PHARMACOLOGY: Pharmacokinetics). While the dose
of flumazenil used for initial reversal of benzodiazepine
effects is not affected, repeat doses of the drug in liver
disease should be reduced in size or frequency.<br/>Use in Drug- and
Alcohol-Dependent Patients: Flumazenil
injection should be used with caution in patients with
alcoholism and other drug dependencies due to the increased
frequency of benzodiazepine tolerance and dependence observed in
these patient populations. Flumazenil
injection is not recommended either as a treatment for
benzodiazepine dependence or for the management of protracted
benzodiazepine abstinence syndromes, as such use has not been
studied. The
administration of flumazenil can precipitate benzodiazepine
withdrawal in animals and man. This has been seen in healthy
volunteers treated with therapeutic doses of oral lorazepam for
up to 2 weeks who exhibited effects such as hot flushes,
agitation and tremor when treated with cumulative doses of up to
3 mg doses of flumazenil. Similar
adverse experiences suggestive of flumazenil precipitation of
benzodiazepine withdrawal have occurred in some adult patients
in clinical trials. Such patients had a short-lived syndrome
characterized by dizziness, mild confusion, emotional lability,
agitation (with signs and symptoms of anxiety), and mild sensory
distortions. This response was dose-related, most common at
doses above 1 mg, rarely required treatment other than
reassurance and was usually short lived. When required, these
patients (5 to 10 cases) were successfully treated with usual
doses of a barbiturate, a benzodiazepine, or other sedative
drug. Practitioners should assume that flumazenil administration may
trigger dose-dependent withdrawal syndromes in patients with
established physical dependence on benzodiazepines and may
complicate the management of withdrawal syndromes for alcohol,
barbiturates and cross-tolerant sedatives.<br/>Drug Interactions: Interaction
with central nervous system depressants other than
benzodiazepines has not been specifically studied; however, no
deleterious interactions were seen when flumazenil injection was
administered after narcotics, inhalational anesthetics, muscle
relaxants and muscle relaxant antagonists administered in
conjunction with sedation or anesthesia. Particular
caution is necessary when using flumazenil injection in cases of
mixed drug overdosage since the toxic effects (such as
convulsions and cardiac dysrhythmias) of other drugs taken in
overdose (especially cyclic antidepressants) may emerge with the
reversal of the benzodiazepine effect by flumazenil (see
WARNINGS). The use of
flumazenil injection is not recommended in epileptic patients
who have been receiving benzodiazepine treatment for a prolonged
period. Although flumazenil injection exerts a slight intrinsic
anticonvulsant effect, its abrupt suppression of the protective
effect of a benzodiazepine agonist can give rise to convulsions
in epileptic patients. Flumazenil
injection blocks the central effects of benzodiazepines by
competitive interaction at the receptor level. The effects of
nonbenzodiazepine agonists at benzodiazepine receptors, such as
zopiclone, triazolopyridazines and others, are also blocked by
flumazenil injection. The
pharmacokinetics of benzodiazepines are unaltered in the
presence of flumazenil and vice versa. There is no
pharmacokinetic interaction between ethanol and
flumazenil.<br/>Use in Ambulatory
Patients: The effects
of flumazenil injection may wear off before a long-acting
benzodiazepine is completely cleared from the body. In general,
if a patient shows no signs of sedation within 2 hours after a 1
mg dose of flumazenil, serious resedation at a later time is
unlikely. An adequate period of observation must be provided for
any patient in whom either long-acting benzodiazepines (such as
diazepam) or large doses of short-acting benzodiazepines (such
as>10 mg of midazolam) have been used . Because of
the increased risk of adverse reactions in patients who have
been taking benzodiazepines on a regular basis, it is
particularly important that physicians query patients or their
guardians carefully about benzodiazepine, alcohol and sedative
use as part of the history prior to any procedure in which the
use of flumazenil injection is planned (see PRECAUTIONS: Use in Drug- and Alcohol-Dependent
Patients).<br/>Information for
Patients: Flumazenil
injection does not consistently reverse amnesia. Patients cannot
be expected to remember information told to them in the
postprocedure period and instructions given to patients should
be reinforced in writing or given to a responsible family
member. Physicians are advised to discuss with patients or their
guardians, both before surgery and at discharge, that although
the patient may feel alert at the time of discharge, the effects
of the benzodiazepine (e.g., sedation) may recur. As a result,
the patient should be instructed, preferably in writing, that
their memory and judgment may be impaired and specifically
advised:<br/>Laboratory Tests: No specific
laboratory tests are recommended to follow the
patient's response or to identify possible adverse
reactions.<br/>Drug/Laboratory
Test Interactions: The
possible interaction of flumazenil with commonly used laboratory
tests has not been evaluated.<br/>Carcinogenesis,
Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: No
studies in animals to evaluate the carcinogenic
potential of flumazenil have been conducted.<br/>Mutagenesis: No
evidence for mutagenicity was noted in the Ames test
using five different tester strains. Assays for
mutagenic potential in S.
cerevisiae D7 and in Chinese hamster cells
were considered to be negative as were blastogenesis
assays in vitro
in peripheral human lymphocytes and in vivo in a mouse
micronucleus assay. Flumazenil caused a slight increase
in unscheduled DNA synthesis in rat hepatocyte culture
at concentrations which were also cytotoxic; no increase
in DNA repair was observed in male mouse germ cells in
an in vivo DNA
repair assay.<br/>Impairment
of Fertility: A
reproduction study in male and female rats did not show
any impairment of fertility at oral dosages of 125
mg/kg/day. From the available data on the area under the
curve (AUC) in animals and man the dose represented 120
times the human exposure from a maximum recommended
intravenous dose of 5 mg.<br/>Pregnancy:<br/>Pregnancy
Category C: There are no adequate and well-controlled studies of
the use of flumazenil in pregnant women. Flumazenil
should be used during pregnancy only if the potential
benefit justifies the potential risk to the
fetus.<br/>Teratogenic
Effects: Flumazenil has been studied for teratogenicity in rats
and rabbits following oral treatments of up to 150
mg/kg/day. The treatments during the major organogenesis
were on days 6 to 15 of gestation in the rat and days 6
to 18 of gestation in the rabbit. No teratogenic effects
were observed in rats or rabbits at 150 mg/kg; the dose,
based on the available data on the area under the plasma
concentration-time curve (AUC) represented 120 times to
600 times the human exposure from a maximum recommended
intravenous dose of 5 mg in humans. In rabbits,
embryocidal effects (as evidenced by increased
preimplantation and postimplantation losses) were
observed at 50 mg/kg or 200 times the human exposure
from a maximum recommended intravenous dose of 5 mg. The
no-effect dose of 15 mg/kg in rabbits represents 60
times the human exposure.<br/>Nonteratogenic Effects: An
animal reproduction study was conducted in rats at oral
dosages of 5, 25 and 125 mg/kg/day of flumazenil. Pup
survival was decreased during the lactating period, pup
liver weight at weaning was increased for the high-dose
group (125 mg/kg/day) and incisor eruption and ear
opening in the offspring were delayed; the delay in ear
opening was associated with a delay in the appearance of
the auditory startle response. No treatment-related
adverse effects were noted for the other dose groups.
Based on the available data from AUC, the effect level
(125 mg/kg) represents 120 times the human exposure from
5 mg, the maximum recommended intravenous dose in
humans. The no-effect level represents 24 times the
human exposure from an intravenous dose of 5
mg.<br/>Labor and Delivery: The use of
flumazenil injection to reverse the effects of benzodiazepines
used during labor and delivery is not recommended because the
effects of the drug in the newborn are unknown.<br/>Nursing Mothers: Caution
should be exercised when deciding to administer flumazenil
injection to a nursing woman because it is not known whether
flumazenil is excreted in human milk.<br/>Pediatric Use: The safety
and effectiveness of flumazenil injection have been established
in pediatric patients 1 year of age and older. Use of flumazenil
injection in this age group is supported by evidence from
adequate and well-controlled studies of flumazenil injection in
adults with additional data from uncontrolled pediatric studies
including one open-label trial. The use of
flumazenil injection to reverse the effects of benzodiazepines
used for conscious sedation was evaluated in one uncontrolled
clinical trial involving 107 pediatric patients between the ages
of 1 and 17 years. At the doses used, the safety of flumazenil
injection was established in this population. Patients received
up to 5 injections of 0.01 mg/kg flumazenil up to a maximum
total dose of 1 mg at a rate not exceeding 0.2 mg/min. Of 60
patients who were fully alert at 10 minutes, 7 experienced
resedation. Resedation occurred between 19 and 50 minutes after
the start of flumazenil injection administration. None of the
patients experienced a return to the baseline level of sedation.
All 7 patients were between the ages of 1 and 5 years. The types
and frequency of adverse events noted in these pediatric
patients were similar to those previously documented in clinical
trials with flumazenil injection to reverse conscious sedation
in adults. No patient experienced a serious adverse event
attributable to flumazenil. The safety
and efficacy of flumazenil injection in the reversal of
conscious sedation in pediatric patients below the age of 1 year
have not been established (see CLINICAL
PHARMACOLOGY: Pharmacokinetics in Pediatric
Patients). The safety
and efficacy of flumazenil injection have not been established
in pediatric patients for reversal of the sedative effects of
benzodiazepines used for induction of general anesthesia, for
the management of overdose, or for the resuscitation of the
newborn, as no well-controlled clinical studies have been
performed to determine the risks, benefits and dosages to be
used. However, published anecdotal reports discussing the use of
flumazenil injection in pediatric patients for these indications
have reported similar safety profiles and dosing guidelines to
those described for the reversal of conscious sedation. The risks
identified in the adult population with flumazenil injection use
also apply to pediatric patients. Therefore, consult the
CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE
REACTIONS sections when using flumazenil
injection in pediatric patients.<br/>Geriatric Use: Of the
total number of subjects in clinical studies of flumazenil, 248
were 65 and over. No overall differences in safety or
effectiveness were observed between these subjects and younger
subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals
cannot be ruled out. The
pharmacokinetics of flumazenil have been studied in the elderly
and are not significantly different from younger patients.
Several studies of flumazenil injection in subjects over the age
of 65 and one study in subjects over the age of 80 suggest that
while the doses of benzodiazepine used to induce sedation should
be reduced, ordinary doses of flumazenil injection may be used
for reversal.
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There is limited
experience of acute overdose with flumazenil injection. There is no
specific antidote for overdose with flumazenil injection. Treatment of
an overdose with flumazenil injection should consist of general
supportive measures including monitoring of vital signs and observation
of the clinical status of the patient. Intravenous bolus
administration of doses ranging from 2.5 to 100 mg (exceeding those
recommended) of flumazenil injection, when administered to healthy
normal volunteers in the absence of a benzodiazepine agonist, produced
no serious adverse reactions, severe signs or symptoms, or clinically
significant laboratory test abnormalities. In clinical studies, most
adverse reactions to flumazenil were an extension of the pharmacologic
effects of the drug in reversing benzodiazepine effects. Reversal with an
excessively high dose of flumazenil injection may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly
convulsions. Convulsions have been treated with barbiturates,
benzodiazepines and phenytoin, generally with prompt resolution of the
seizures .
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Flumazenil
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Flumazenil (Injection, Solution)
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Serious Adverse
Reactions: Deaths have
occurred in patients who received flumazenil injection in a
variety of clinical settings. The majority of deaths occurred in
patients with serious underlying disease or in patients who had
ingested large amounts of non-benzodiazepine drugs (usually
cyclic antidepressants), as part of an overdose. Serious
adverse events have occurred in all clinical settings, and
convulsions are the most common serious adverse events reported.
Flumazenil injection administration has been associated with the
onset of convulsions in patients with severe hepatic impairment
and in patients who are relying on benzodiazepine effects to
control seizures, are physically dependent on benzodiazepines,
or who have ingested large doses of other drugs (mixed-drug
overdose) . Two of the
446 patients who received flumazenil injection in controlled
clinical trials for the management of a benzodiazepine overdose
had cardiac dysrhythmias (1 ventricular tachycardia, 1
junctional tachycardia).<br/>Adverse Events in
Clinical Studies: The
following adverse reactions were considered to be related to
flumazenil injection administration (both alone and for the
reversal of benzodiazepine effects) and were reported in studies
involving 1875 individuals who received flumazenil in controlled
trials. Adverse events most frequently associated with
flumazenil alone were limited to dizziness, injection site pain,
increased sweating, headache, and abnormal or blurred vision (3%
to 9%). Body as a Whole:fatigue
(asthenia, malaise), headache, injection site pain*, injection
site reaction (thrombophlebitis, skin abnormality, rash) Cardiovascular
System:cutaneous vasodilation (sweating, flushing, hot
flushes) Digestive System:nausea,
vomiting (11%) Nervous System:agitation
(anxiety, nervousness, dry mouth, tremor, palpitations,
insomnia, dyspnea, hyperventilation)*, dizziness (vertigo,
ataxia) (10%), emotional lability (crying abnormal,
depersonalization, euphoria, increased tears, depression,
dysphoria, paranoia) Special Senses:abnormal vision
(visual field defect, diplopia), paresthesia (sensation
abnormal, hypoesthesia) All adverse
reactions occurred in 1% to 3% of cases unless otherwise marked. *indicates
reaction in 3% to 9% of cases. Observed
percentage reported if greater than 9%. The
following adverse events were observed infrequently (less than
1%) in the clinical studies, but were judged as probably related
to flumazenil injection administration and/or reversal of
benzodiazepine effects: Nervous System:confusion
(difficulty concentrating, delirium), convulsions and somnolence (stupor) Special Senses:abnormal
hearing (transient hearing impairment, hyperacusis, tinnitus) The
following adverse events occurred with frequencies less than 1%
in the clinical trials. Their relationship to flumazenil
injection administration is unknown, but they are included as
alerting information for the physician. Body as a Whole:rigors,
shivering Cardiovascular
System:arrhythmia (atrial, nodal, ventricular
extrasystoles), bradycardia, tachycardia, hypertension, chest
pain Digestive System: hiccup Nervous System:speech disorder
(dysphonia, thick tongue) Not
included in this list is operative site pain that occurred with
the same frequency in patients receiving placebo as in patients
receiving flumazenil for reversal of sedation following a
surgical procedure.<br/>Additional Adverse
Reactions Reported During Postmarketing Experience: The
following events have been reported during postapproval use of
flumazenil injection. Nervous System: Fear, panic
attacks in patients with a history of panic disorders. Withdrawal
symptoms may occur following rapid injection of flumazenil
injection in patients with long-term exposure to
benzodiazepines.
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THE USE OF FLUMAZENIL INJECTION HAS BEEN
ASSOCIATED WITH THE OCCURRENCE OF SEIZURES. THESE ARE MOST FREQUENT IN PATIENTS WHO HAVE
BEEN ON BENZODIAZEPINES FOR LONG-TERM SEDATION OR IN OVERDOSE CASES
WHERE PATIENTS ARE SHOWING SIGNS OF SERIOUS CYCLIC ANTIDEPRESSANT
OVERDOSE. PRACTITIONERS SHOULD INDIVIDUALIZE THE DOSAGE
OF FLUMAZENIL INJECTION AND BE PREPARED TO MANAGE
SEIZURES.<br/>Risk of Seizures: The reversal of benzodiazepine effects
may be associated with the onset of seizures in certain
high-risk populations. Possible risk factors for seizures
include: concurrent major sedative-hypnotic drug withdrawal,
recent therapy with repeated doses of parenteral
benzodiazepines, myoclonic jerking or seizure activity prior
to flumazenil administration in overdose cases, or
concurrent cyclic antidepressant poisoning. Flumazenil injection is not
recommended in cases of serious cyclic antidepressant
poisoning, as manifested by motor abnormalities (twitching,
rigidity, focal seizure), dysrhythmia (wide QRS, ventricular
dysrhythmia, heart block), anticholinergic signs (mydriasis,
dry mucosa, hypoperistalsis), and cardiovascular collapse at
presentation. In such cases flumazenil injection should be
withheld and the patient should be allowed to remain sedated
(with ventilatory and circulatory support as needed) until
the signs of antidepressant toxicity have subsided.
Treatment with flumazenil injection has no known benefitto
the seriously ill mixed-overdose patient other than
reversing sedation and should not be used in cases where
seizures (from any cause) are likely. Most convulsions associated with
flumazenil administration require treatment and have been
successfully managed with benzodiazepines, phenytoin or
barbiturates. Because of the presence of flumazenil, higher
than usual doses of benzodiazepines may be required.<br/>Hypoventilation: Patients who have received flumazenil
injection for the reversal of benzodiazepine effects (after
conscious sedation or general anesthesia) should be
monitored for resedation, respiratory depression, or other
residual benzodiazepine effects for an appropriate period
(up to 120 minutes) based on the dose and duration of effect
of the benzodiazepine employed. This is because flumazenil injection
has not been established in patients as an effective
treatment for hypoventilation due to benzodiazepine
administration. In healthy male volunteers, flumazenil
injection is capable of reversing benzodiazepine-induced
depression of the ventilatory responses to hypercapnia and
hypoxia after a benzodiazepine alone. However, such
depression may recur because the ventilatory effects of
typical doses of flumazenil injection (1 mg or less) may
wear off before the effects of many benzodiazepines. The
effects of flumazenil injection on ventilatory response
following sedation with a benzodiazepine in combination with
an opioid are inconsistent and have not been adequately
studied. The availability of flumazenil does not diminish
the need for prompt detection of hypoventilation and the
ability to effectively intervene by establishing an airway
and assisting ventilation. Overdose cases should always be
monitored for resedation until the patients are stable and
resedation is unlikely.
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Adult Patients: Flumazenil
injection is indicated for the complete or partial reversal of
the sedative effects of benzodiazepines in cases where general
anesthesia has been induced and/or maintained with
benzodiazepines, where sedation has been produced with
benzodiazepines for diagnostic and therapeutic procedures, and
for the management of benzodiazepineoverdose.<br/>Pediatric Patients
(aged 1 to 17): Flumazenil
injection is indicated for the reversal of conscious sedation
induced with benzodiazepines .
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Flumazenil
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