A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Versed Side Effects, and Drug Interactions - Midazolam
Versed Side Effects, and Drug Interactions - Midazolam
SIDE EFFECTS
See WARNINGSconcerning serious cardiorespiratory events and
possible paradoxical reactions. Fluctuations in vital signs were the most
frequently seen findings following parenteral administration of VERSED in adults
and included decreased tidal volume and/or respiratory rate decrease (23.3%
of patients following IV and 10.8% of patients following IM administration)
and apnea (15.4% of patients following IV administration), as well as variations
in blood pressure and pulse rate. The majority of serious adverse effects, particularly
those associated with oxygenation and ventilation, have been reported when VERSED
is administered with other medications capable of depressing the central nervous
system. The incidence of such events is higher in patients undergoing procedures
involving the airway without the protective effect of an endotracheal tube (eg,
upper endoscopy and dental procedures).
Adults: The following additional adverse reactions
were reported after intramuscular administration:
headache (1.3%)
Local effects at IM Injection site
pain (3.7%)
induration (0.5%)
redness (0.5%)
muscle stiffness (0.3%)
Administration of IM VERSED to elderly and/or higher risk surgical patients
has been associated with rare reports of death under circumstances compatible
with cardiorespiratory depression. In most of these cases, the patients also
received other central nervous system depressants capable of depressing respiration,
especially narcotics (see DOSAGE AND ADMINISTRATION ).
The following additional adverse reactions were reported subsequent to intravenous
administration as a single sedative/anxiolytic/amnestic agent in adult patients:
hiccoughs (3.9%)
nausea (2.8%)
vomiting (2.6%)
coughing (1.3%)
"oversedation" (1.6%)
headache (1.5%)
drowsiness (1.2%)
Local effects at the IV site
tenderness (5.6%)
pain during injection (5.0%)
redness (2.6%)
induration (1.7%)
phlebitis (0.4%)
Pediatric Patients: The following adverse events
related to the use of IV VERSED in pediatric patients were reported in the medical
literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions
2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority
of airway-related events occurred in patients receiving other CNS depressing
medications and in patients where VERSED was not used as a single sedating agent.
Neonates: For information concerning hypotensive
episodes and seizures following the administration of VERSED to neonates (see
Boxed WARNING , CONTRAINDICATIONS , WARNINGS and PRECAUTIONS).
Other adverse experiences, observed mainly following IV injection as a single
sedative/anxiolytic/amnesia agent and occurring at an incidence of <1.0%
in adult and pediatric patients, are as follows:
Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation,
wheezing, shallow respirations, airway obstruction, tachypnea
Cardiovascular: Bigeminy, premature ventricular contractions,
vasovagal episode, bradycardia, tachycardia, nodal rhythm
Gastrointestinal: Acid taste, excessive salivation, retching
CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion,
argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence
delirium or agitation, prolonged emergence from anesthesia, dreaming during
emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like
activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia
Special Senses: Blurred vision, diplopia, nystagmus, pinpoint
pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing
eyes, ears blocked, loss of balance, light-headedness
Integumentary: Hive-like elevation at injection site, swelling
or feeling of burning, warmth or coldness at injection site
Hypersensitivity: Allergic reactions including anaphylactoid
reactions, hives, rash, pruritus
Miscellaneous: Yawning, lethargy, chills, weakness, toothache,
faint feeling, hematoma
DRUG ABUSE AND DEPENDENCE
Midazolam is subject to Schedule IV control under the Controlled Substances
Act of 1970.
Midazolam was actively self-administered in primate models used to assess the
positive reinforcing effects of psychoactive drugs.
Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus
monkeys after 5 to 10 weeks of administration. Available data concerning the
drug abuse and dependence potential of midazolam suggest that its abuse potential
is at least equivalent to that of diazepam.
Withdrawal symptoms, similar in character to those noted with barbiturates
and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps,
vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines,
including midazolam. Abdominal distention, nausea, vomiting, and tachycardia
are prominent symptoms of withdrawal in infants. The more severe withdrawal
symptoms have usually been limited to those patients who had received excessive
doses over an extended period of time. Generally milder withdrawal symptoms
(eg, dysphoria and insomnia) have been reported following abrupt discontinuance
of benzodiazepines taken continuously at therapeutic levels for several months.
Consequently, after extended therapy, abrupt discontinuation should generally
be avoided and a gradual dosage tapering schedule followed. There is no consensus
in the medical literature regarding tapering schedules; therefore, practitioners
are advised to individualize therapy to meet patient's needs. In some case reports,
patients who have had severe withdrawal reactions due to abrupt discontinuation
of high-dose long-term midazolam, have been successfully weaned off of midazolam
over a period of several days.
DRUG INTERACTIONS
Drug Interactions: The sedative effect of intravenous
VERSED is accentuated by any concomitantly administered medication, which depresses
the central nervous system, particularly narcotics (eg, morphine, meperidine
and fentanyl) and also secobarbital and droperidol. Consequently, the dosage
of VERSED should be adjusted according to the type and amount of concomitant
medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION).
Caution is advised when midazolam is administered concomitantly with drugs
that are known to inhibit the P450 3A4 enzyme system such as cimetidine (not
ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.
These drug interactions may result in prolonged sedation due to a decrease in
plasma clearance of midazolam.
The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine
on steady-state concentrations of midazolam was examined in a randomized crossover
study (n=8). Cimetidine increased the mean midazolam steady-state concentration
from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration
to 62 ng/mL. No change in choice reaction time or sedation index was detected
after dosing with the H2 receptor antagonists.
In a placebo-controlled study, erythromycin administered as a 500 mg dose,
tid, for 1 week (n=6), reduced the clearance of midazolam following a single
0.5 mg/kg IV dose. The half-life was approximately doubled.
Caution is advised when midazolam is administered to patients receiving erythromycin
since this may result in a decrease in the plasma clearance of midazolam.
The effects of diltiazem (60 mg tid) and verapamil (80 mg tid) on the pharmacokinetics
and pharmacodynamics of midazolam were investigated in a three-way crossover
study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam
was taken in conjunction with verapamil or diltiazem. No interaction was observed
in healthy subjects between midazolam and nifedipine.
In a placebo-controlled study, saquinvair administered as a 1200 mg dose, tid,
for 5 days (n=12), a 56% reduction in the clearance of midazolam following a
single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.
A moderate reduction in induction dosage requirements of thiopental (about
15%) has been noted following use of intramuscular VERSED for premedication
in adults.
The intravenous administration of VERSED decreases the minimum alveolar concentration
(MAC) of halothane required for general anesthesia. This decrease correlates
with the dose of VERSED administered; no similar studies have been carried out
in pediatric patients but there is no scientific reason to expect that pediatric
patients would respond differently than adults.
Although the possibility of minor interactive effects has not been fully studied,
VERSED and pancuronium have been used together in patients without noting clinically
significant changes in dosage, onset or duration in adults. VERSED does not
protect against the characteristic circulatory changes noted after administration
of succinylcholine or pancuronium and does not protect against the increased
intracranial pressure noted following administration of succinylcholine. VERSED
does not cause a clinically significant change in dosage, onset or duration
of a single intubating dose of succinylcholine; no similar studies have been
carried out in pediatric patients but there is no scientific reason to expect
that pediatric patients would respond differently than adults.
No significant adverse interactions with commonly used premedications or drugs
used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate,
diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing
muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine
HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates,
however, severe hypotension has been reported with concomitant administration
of fentanyl. This effect has been observed in neonates on an infusion of midazolam
who received a rapid injection of fentanyl and in patients on an infusion of
fentanyl who have received a rapid injection of midazolam.
Drug/Laboratory Test Interactions: Midazolam has
not been shown to interfere with results obtained in clinical laboratory tests.
top
