SUBLIMAZE

SUBLIMAZE- fentanyl citrate injection, solution
Taylor Pharmaceuticals

CII

Rx only

DESCRIPTION

SUBLIMAZE (fentanyl citrate) Injection is a potent narcotic analgesic. Each milliliter of solution contains fentanyl citrate equivalent to 50 mcg of fentanyl base, adjusted to pH 4.0 to 7.5 with sodium hydroxide. SUBLIMAZE is chemically identified as N-(1-phenethyl-4-piperidyl) propionanilide citrate (1:1) with a molecular weight of 528.60. The empirical formula is C22 H28 N2 O • C6 H8 O7 . The structural formula of SUBLIMAZE is:

Chemical Structure
(click image for full-size original)

SUBLIMAZE is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or intramuscular injection.

CLINICAL PHARMACOLOGY

SUBLIMAZE (fentanyl citrate) is a narcotic analgesic. A dose of 100 mcg (0.1 mg) (2.0 ml) is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with narcotic analgesics, may last longer than the analgesic effect. As the dose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea. SUBLIMAZE appears to have less emetic activity than either morphine or meperidine. Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with SUBLIMAZE. Recent assays in man show no clinically significant histamine release in dosages up to 50 mcg/kg (0.05 mg/kg) (1 ml/kg). SUBLIMAZE preserves cardiac stability, and blunts stress-related hormonal changes at higher doses.

The pharmacokinetics of SUBLIMAZE can be described as a three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for SUBLIMAZE is 4 L/kg.

SUBLIMAZE plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and is released slowly into the blood. SUBLIMAZE, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

The onset of action of SUBLIMAZE is almost immediate when the drug is given intravenously; however, the maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg (0.1 mg) (2.0 ml). Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours. As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of SUBLIMAZE may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of SUBLIMAZE to man.

  1. DIMINISHED SENSITIVITY TO CO2 STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF RESPIRATORY RATE. (Altered sensitivity to CO2 stimulation has been demonstrated for up to four hours following a single dose of 600 mcg (0.6 mg) (12 ml) SUBLIMAZE to healthy volunteers.) SUBLIMAZE frequently slows the respiratory rate, duration and degree of respiratory depression being dose related.
  2. The peak respiratory depressant effect of a single intravenous dose of SUBLIMAZE is noted 5 to 15 minutes following injection. See also WARNINGS and PRECAUTIONS concerning respiratory depression.

SUBLIMAZE Indications and Usage

SUBLIMAZE (fentanyl citrate) is indicated:

for analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises.
for use as a narcotic analgesic supplement in general or regional anesthesia.
for administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.
for use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

CONTRAINDICATIONS

SUBLIMAZE (fentanyl citrate) is contraindicated in patients with known intolerance to the drug or other opioid agonists.

WARNINGS

SUBLIMAZE (fentanyl citrate) SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS.

AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE.

See also discussion of narcotic antagonists in PRECAUTIONS and OVERDOSAGE.

If SUBLIMAZE is administered with a tranquilizer, the user should become familiar with the special properties of each drug, particularly the widely differing duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.

As with other potent narcotics, the respiratory depressant effect of SUBLIMAZE may persist longer than the measured analgesic effect. The total dose of all narcotic analgesics administered should be considered by the practitioner before ordering narcotic analgesics during recovery from anesthesia. It is recommended that narcotics, when required, should be used in reduced doses initially, as low as ¼ to ⅓ those usually recommended.

SUBLIMAZE may cause muscle rigidity, particularly involving the muscles of respiration. This rigidity has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck and external eye have been reported during induction of anesthesia with fentanyl; these reported movements have, on rare occasions, been strong enough to pose patient management problems. This effect is related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to ¼ of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of SUBLIMAZE; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when SUBLIMAZE is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of SUBLIMAZE and a full paralyzing dose of a neuromuscular blocking agent when SUBLIMAZE is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status.

Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of SUBLIMAZE. Where moderate or high doses are used (above 10 mcg/kg), there must be adequate facilities for postoperative observation, and ventilation if necessary, of patients who have received SUBLIMAZE. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.

SUBLIMAZE may also produce other signs and symptoms characteristic of narcotic analgesics including euphoria, miosis, bradycardia and bronchoconstriction.

Severe and unpredictable potentiation by MAO inhibitors has been reported for other narcotic analgesics. Although this has not been reported for fentanyl, there are insufficient data to establish that this does not occur with fentanyl. Therefore, when fentanyl is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is indicated.

Head Injuries and Increased Intracranial Pressure

SUBLIMAZE should be used with caution in patients who may be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain tumor. In addition, SUBLIMAZE may obscure the clinical course of patients with head injury.

PRECAUTIONS

General

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 activity.

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 (MAOI’s), 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 CO2 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 CO2 . 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 area.

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