The initial dose of SUBLIMAZE (fentanyl citrate) should be appropriately reduced
in elderly and debilitated patients. The effect of the initial dose should be
considered in determining incremental doses.
Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of SUBLIMAZE.
Certain forms of conduction anesthesia, such as spinal anesthesia and some
peridural anesthetics, can alter respiration by blocking intercostal nerves.
Through other mechanisms (see CLINICAL PHARMACOLOGY) SUBLIMAZE can also
alter respiration. Therefore, when SUBLIMAZE is used to supplement these forms
of anesthesia, the anesthetist should be familiar with the physiological alterations
involved, and be prepared to manage them in the patients selected for these
forms of anesthesia.
When a tranquilizer is used with SUBLIMAZE, pulmonary arterial pressure may
be decreased. This fact should be considered by those who conduct diagnostic
and surgical procedures where interpretation of pulmonary arterial pressure
measurements might determine final management of the patient. When high dose
or anesthetic dosages of SUBLIMAZE are employed, even relatively small dosages
of diazepam may cause cardiovascular depression.
When SUBLIMAZE is used with a tranquilizer, hypotension can occur. If it occurs,
the possibility of hypovolemia should also be considered and managed with appropriate
parenteral fluid therapy. Repositioning the patient to improve venous return
to the heart should be considered when operative conditions permit. Care should
be exercised in moving and repositioning of patients because of the possibility
of orthostatic hypotension. If volume expansion with fluids plus other countermeasures
do not correct hypotension, the administration of pressor agents other than
epinephrine should be considered. Epinephrine may paradoxically decrease blood
pressure in patients treated with a neuroleptic that blocks alpha adrenergic
Elevated blood pressure, with and without pre-existing hypertension, has been
reported following administration of SUBLIMAZE combined with a neuroleptic.
This might be due to unexplained alterations in sympathetic activity following
large doses; however, it is also frequently attributed to anesthetic and surgical
stimulation during light anesthesia. When SUBLIMAZE is used with a neuroleptic
and the EEG is used for postoperative monitoring, it may be found that the EEG
pattern returns to normal slowly.
Many neuroleptic agents have been associated with QT prolongation, torsades
de pointes, and cardiac arrest. Neuroleptic agents should be administered with
extreme caution in the presence of risk factors for development of prolonged
QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia
(less than 50 bpm), 2) any clinically significant cardiac disease, including
baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics,
4) treatment with monoamine oxidase inhibitors (MAOIs), 5) concomitant treatment
with other drug products known to prolong the QT interval and 6) electrolyte
imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment
with drugs (e.g. diuretics) that may cause electrolyte imbalance.
ECG monitoring is indicated when a neuroleptic agent is used in conjunction
with SUBLIMAZE as an anesthetic premedication, for the induction of anesthesia,
or as an adjunct in the maintenance of general or regional anesthesia.
Vital signs should be monitored routinely.
Respiratory depression caused by opioid analgesics can be reversed by opioid
antagonists such as naloxone. Because the duration of respiratory depression
produced by SUBLIMAZE may last longer than the duration of the opioid antagonist
action, appropriate surveillance should be maintained. As with all potent opioids,
profound analgesia is accompanied by respiratory depression and diminished sensitivity
to COi stimulation which may persist into or recur in the postoperative period.
Respiratory depression secondary to chest wall rigidity has been reported in
the postoperative period. Intraoperative hyperventilation may further alter
postoperative response to C02- Appropriate postoperative monitoring should be
employed to ensure that adequate spontaneous breathing is established and maintained
in the absence of stimulation prior to discharging the patient from the recovery
SUBLIMAZE should be used with caution in patients with chronic obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such patients, narcotics may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration.
Impaired Hepatic or Renal Function
SUBLIMAZE should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs.
SUBLIMAZE may produce bradycardia, which may be treated with atropine. SUBLIMAZE should be used with caution in patients with cardiac bradyarrhythmias.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or mutagenicity studies have been conducted with SUBLIMAZE. Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental groups. This decrease was most pronounced in the high dosed group (1.25 mg/kg — 12.5X human dose) in which one of twenty animals became pregnant.
SUBLIMAZE has been shown to impair fertility and to have an embryocidal effect in rats when given in doses 0.3 times the upper human dose for a period of 12 days. No evidence of teratogenic effects have been observed after administration of SUBLIMAZE to rats. There are no adequate and well-controlled studies in pregnant women. SUBLIMAZE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
There are insufficient data to support the use of SUBLIMAZE in labor and delivery. Therefore, such use is not recommended.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SUBLIMAZE is administered to a nursing woman.
The safety and efficacy of SUBLIMAZE in children under two years of age have not been established.
Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included the combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.