Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/635
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Romazicon (Injection, Solution)
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ROMAZICON is recommended
for intravenous use only. It is compatible with 5% dextrose in water,
lactated Ringer's and normal saline solutions. If ROMAZICON is
drawn into a syringe or mixed with any of these solutions, it should
be discarded after 24 hours. For optimum sterility, ROMAZICON should
remain in the vial until just before use. As with all parenteral drug
products, ROMAZICON 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, ROMAZICON 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 ROMAZICON 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 ROMAZICON 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/>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 1.00 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 ROMAZICON administration . The safety and efficacy of repeated flumazenil administration
in pediatric patients experiencing resedation have not been established. It is recommended
that ROMAZICON 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 ROMAZICON 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 ROMAZICON 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 further 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
ROMAZICON 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 ROMAZICON 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 ROMAZICON. 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 ROMAZICON, 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 ROMAZICON, the major cause of sedation is likely not
to be due to benzodiazepines, and additional ROMAZICON 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: ROMAZICON 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.
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| dailymed-instance:descripti... |
ROMAZICON (flumazenil) 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, a calculated molecular weight of 303.3, 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. ROMAZICON 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 approximately 4 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 haslittle 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,
ROMAZICON elicited symptoms of benzodiazepine withdrawal, including
seizures. A similar effect was seen in adult human subjects.<br/>Pharmacodynamics: Intravenous ROMAZICON
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 occurring at 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 ROMAZICON given. In healthy volunteers,
ROMAZICON 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 1.0 L/hr/kg. Pharmacokinetic
parameters following a 5-minute infusion of a total of 1 mg of ROMAZICON
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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5 mL multiple-use vials
containing 0.1 mg/mL flumazenil���boxes of 10 (NDC 0004-6911-06);
10 mL multiple-use vials containing 0.1 mg/mL flumazenil���boxes of 10 (NDC 0004-6912-06).<br/>Storage: Store at 25��C
(77��F); excursions permitted to 15��to 30��C (59��to 86��F) [See USP Controlled Room Temperature].
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THE USE OF ROMAZICON 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 ROMAZICON AND BE PREPARED TO MANAGE
SEIZURES.
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There is limited experience
of acute overdose with ROMAZICON. There is no specific antidote for overdose with ROMAZICON.
Treatment of an overdose with ROMAZICON 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 ROMAZICON, 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 anextension of
the pharmacologic effects of the drug in reversing benzodiazepine
effects. Reversal with
an excessively high dose of ROMAZICON 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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Romazicon (Injection, Solution)
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Serious Adverse Reactions: Deaths have occurred
in patients who received ROMAZICON 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. ROMAZICON 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 ROMAZICON 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 ROMAZICON 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. 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
ROMAZICON administration and/or reversal of benzodiazepine effects: Nervous System: confusion (difficulty
concentrating, delirium), convulsions , 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 ROMAZICON 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 ROMAZICON. Nervous System: Fear, panic attacks
in patients with a history of panic disorders. Withdrawal symptoms may occur following rapid injection of ROMAZICON
in patients with long-term exposure to benzodiazepines.
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Adult Patients: ROMAZICON 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 benzodiazepine overdose.<br/>Pediatric Patients (aged 1 to 17): ROMAZICON is indicated
for the reversal of conscious sedation induced with benzodiazepines
.
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Romazicon
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