CAUTION: FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION
SUBLIMAZE (fentanyl citrate) injection is a potent narcotic analgesic. Each milliliter of solution contains fentanyl citrate equivalent to 50 mcgm of fentanyl base, adjusted to pH 4.0-7.5 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 C22H28N2O.C6H8O7.
SUBLIMAZE is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or intramuscular injection.
SUBLIMAZE (fentanyl citrate) is a narcotic analgesic. A dose of 100 mcgm (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 mcgm/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 eliminatistribution 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 mcgm (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 mcgm (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 (fentanyl citrate) is indicated:
SUBLIMAZE (fentanyl citrate) is contraindicated in patients with known intolerance to the drug.
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 such as INAPSINE (droperidol), 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 1/4 to 1/3 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:
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 mcgm/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.
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 ACTIONS/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 such as INAPSINE (droperidol) 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 such as INAPSINE (droperidol), hypotension can occur. If it occurs, the possibility of hypovolemia should also be considered and managed with 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 positioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, the administration of presot correct hypotension, the administration of pressor agents other than epinephrine should be considered. Because of the alpha-adrenergic blocking action of INAPSINE (droperidol), epinephrine may paradoxically decrease the blood pressure in patients treated with INAPSINE (droperidol). Elevated blood pressure, with and without pre- existing hypertension, has been reported following administration of SUBLIMAZE combined with INAPSINE (droperidol). 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 INAPSINE (droperidol) is used with SUBLIMAZE and the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly. 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.
Category C: 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 has 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.
There are insufficient data to support the use of SUBLIMAZE in labor and delivery. Therefore, such use is not recommended. NURSING MOTHERS: 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.
PEDIATRIC USE: The safety and efficacy of SUBLIMAZE in children under two years of age has not been established. Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included 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.
Other CNS depressant drugs (e.g. barbiturates, tranquilizers, narcotics and general anesthetics) will have additive or potentiating effects with SUBLIMAZE. When patients have received such drugs, the dose of SUBLIMAZE required will be less than usual. Following the administration of SUBLIMAZE, the dose of other CNS depressant drugs should be reduced. (See Also PRECAUTIONS)
As with other narcotic analgesics, the most common serious adverse reactions reported to occur with SUBLIMAZE (fentctions reported to occur with SUBLIMAZE (fentanyl citrate) are respiratory depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are vision, nausea, emesis, laryngospasm, and diaphoresis. It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary. When a tranquilizer such as INAPSINE (droperidol) is used with SUBLIMAZE, the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti- parkinson agents. Postoperative drowsiness is also frequently reported following the use of INAPSINE (droperidol).
DRUG ABUSE AND DEPENDENCE: SUBLIMAZE (fentanyl citrate) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused.
OVERDOSAGE: Manifestations: The manifestations of SUBLIMAZE (fentanyl citrate) overdosage are an extension of its pharmacologic actions (see ACTIONS/CLINICAL PHARMACOLOGY) as with other opioid analgesics. The intravenous LD50 of SUBLIMAZE is 3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs and rats, 1 mg/kg in cats, 14 mg/kg in dogs and 0.03 mg/kg in monkeys. Treatment: In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. A specific narcotic antagonist such as nalorphine, levallorphan or naloxone should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression following overdosage of SUBLIMAZE may be longer than the duration of narcotic antagonist action. Consult the package insert of the individual narcotic antagonists for details about use.
DOSAGE AND ADMINISTRATION: 50 mcgm = 0.05 mg = 1 ml Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used and the surgical procedure involved. Dosage should be reduced in elderly or debilitated patients (see PRECAUTIONS). Vital signs should be monitored routinely.