SUFENTA FORTE

Injection, USP is a sterile, nonpyrogenic solution of sufentanil citrate in water for injection.

Citrate is a potent opioid analgesic which is administered either epidurally or by intravenous injection.

Each mL contains sufentanil citrate equivalent to 50 mcg of sufentanil.

May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 4.2 (3.5 to 6.0).

The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-use injection.

When smaller doses are required, the unused portion should be discarded in an appropriate manner.

Citrate, USP, occurs as a white crystalline powder and is chemically designated as N -[-4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl].

• N -phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1).

The molecular formula of sufentanil citrate is C 22 H 30 N 2 O 2 S∙C 6 H 8 O and the molecular weight is 578.69.

Sufentanil Citrate has the following structural formula: Chemical Structure.

Central analgesic for anesthesia-resuscitation, sufentanil may be used in the following indications: In adult.

• as an auxiliary analgesic for maintenance of a general anaesthesia with a medium or long-term swing in combination with a hypnotic and (or) a volatile anaesthetic agent and a myorelaxant agent;

• as a primary anaesthetic agent for induction and maintenance of analgesic anaesthesia with 100% oxygen during major surgical procedures such as cardiovascular surgery;

• in peridural administration, single or repeated dose or infusion, alone or in combination with a local anaesthetic for surgical, obstetric or post-operative analgesia;

• in prolonged sedation in intensive care or resuscitation, of patients ventilated;

• in intravenous administration, as a general anaesthetic for anaesthetic surgery, as a general anaesthetic for anaesthetic surgery, as a more severe and post-operative procedure in a unit of intensive care or resuscitation;

• in children.

• in intravenous administration, as a general anaesthetic for anaesthetic for an.

The following are examples of the studies performed: the time taken to extubate or resume spontaneous ventilation after the infusion was between and 8 hours for most patients, for durations of administration of 12-18 hours, and doses of 1-2 micrograms/kg/hour.

The administration of this medicine is not recommended with alcoholic beverages, with medicines containing alcohol and with sodium oxybate, may be of a high degree of renal disease.

Sufentanil is an opioid agonist.

When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl.

When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately to 7 times as potent as fentanyl. 12.2 Pharmacodynamics Effects on the Central Nervous System Sufentanil produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Sufentanil causes miosis, even in total darkness.

Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings).

Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Sufentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.

Digestion of food in the small intestine is delayed and propulsive contractions are decreased.

Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).

Sufentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models.

The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists.

The minimum effective analgesic concentration of sufentanil for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

Concentration–Adverse Reaction Relationships There is a relationship between increasing sufentanil plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. 12.3 Pharmacokinetics Sufentanil Citrate Injection is administered by the intravenous or epidural route.

The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model.

After epidural administration of incremental doses totaling to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants.

Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates.

Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes.

The elimination half-life is 164 minutes in adults.

The elimination half-life of sufentanil is shorter (e.g., 97 +/ - 42 minutes) in infants and children, and longer in neonates (e.g., 434 +/ - 160 minutes) compared to that of adolescents and adults.

The liver and small intestine are the major sites of biotransformation.

Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

The following are the following: opioid anesthetic anaesthetic group (N01AH03) pharmacotherapy group (NMP) pharmacologic group (NMP) pharmaceutical group (NMP) pharmacologic group (NMP) pharmaceutical group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmacologic group (NMP) pharmaceu.

The safety of the sufentanil was evaluated in 650 patients treated with sufentanil in 6 clinical trials.

Of these patients, 78 were involved in two studies in which sufentanil was administered Intravenous for the induction and maintenance of l-anesthetic in patients undergoing major surgery (coronary or open heart surgery).

The other 572 patients were involved in 4 studies in which sufentanil was administered peridurally as postoperative analgesic or as an adjuvant analgesic to bupivacaine during labour and delivery.

These patients received at least one dose of sufentanil and were included in the analysis of the safety data.

On the basis of the low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-

Acute overdose with sufentanil can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death.

Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.

Cardiac arrest or arrhythmias will require advanced life-support measures.

For clinically significant respiratory or circulatory depression secondary to sufentanil overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene.

Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in Sufentanil Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished.

If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information.

In an individual physically-dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome.

The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered.

If a decision is made to treat serious respiratory depression in the physically-dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

• Hypersensitivity to sufentanil (e.g., anaphylaxis).

• Hypersensitivity to sufentanil.

• Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

• Ensure that an opioid overdose reversal agent, resuscitative and intubation equipment, and oxygen are readily available.

• Individualize dosing based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

• Initiate analgesic treatment with to 2 mcg/kg intravenously.

• Initiate epidural injection for labor and delivery at to 15 mcg of Sufentanil administered with 10 mL bupivacaine 0.125% with or without epinephrine. 2.1 Important Dosage and Administration Instructions Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of intravenous or epidural anesthetics and management of the respiratory effects of potent opioids.

In patients administered high doses of Sufentanil Citrate Injection, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression.

For purposes of administering small volumes of Sufentanil Citrate Injection accurately, the use of a tuberculin syringe or equivalent is recommended.

• Ensure that an opioid overdose reversal agent (e.g., naloxone, nalmefene) , resuscitative and intubation equipment, and oxygen are readily available.

• Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

• Monitor vital signs regularly.

• The selection of preanesthetic medications should be based upon the needs of the individual patient.

• The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required.

As with other potent opioids, the respiratory depressant effect of sufentanil may persist longer than the measured analgesic effect.

The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

If Sufentanil Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product's duration of action.

In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Intravenous use Sufentanil Citrate may be administered intravenously by slow injection or infusion.

• Doses of up to 8 mcg/kg.

• Total Dosage Requirements of 1 mcg/kg/hr or less are recommended.

• Dosage should be individualized and adjusted to remaining operative time anticipated.

Table 1: Adult Dosage Range Chart, Analgesic Component To General Anesthesia, Intravenous Use Total dosage Maintenance dosage Duration of anesthesia to 2 hours Incremental or Infusion: 1 to 2 mcg/kg Approximately 75% or more of total sufentanil dosage may be administered prior to intubation by either slow injection or infusion titrated to individual patient response.

Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required.

Incremental: 10 to 25 mcg (0.2 to 0.5 mL) may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.

Supplemental dosages should be individualized and adjusted to remaining operative time anticipated.

Intermittent or continuous infusion as needed in response to signs of lightening of analgesia.

In absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.

Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time.

Duration of anesthesia to 8 hours Incremental or Infusion: 2 to 8 mcg/kg Approximately 75% or less of the total calculated sufentanil dosage may be administered by slow injection or infusion prior to intubation, titrated to individual patient response.

Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures in which endotracheal intubation and mechanical ventilation are required.

At dosages in this range, sufentanil has been shown to provide some attenuation of sympathetic reflex activity in response to surgical stimuli, provide hemodynamic stability, and provide relatively rapid recovery.

Incremental: 10 to 50 mcg (0.2 to 1 mL) may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.

Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated.

In the absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.

• As the primary anesthetic agent: doses ≥8 mcg/kg See Dosage Range Chart, Table 2.

• Dosage should be titrated to individual patient response.

• In children less than 12 years of age undergoing cardiovascular surgery: 10 to 25 mcg/kg administered with 100% oxygen o Supplemental dosages of up to to 50 mcg are recommended for maintenance, based on response to initial dose and as determined by changes in vital signs indicating surgical stress or lightening of anesthesia.

Table 2: Dosage Range Chart, Induction and Maintenance of Anesthesia, Intravenous Use Incremental or Infusion: 8 to 30 mcg/kg Generally administered as a slow injection, as an infusion, or as an injection followed by an infusion.

Sufentanil with 100% oxygen and a muscle relaxant has been found to produce sleep at dosages ≥8 mcg/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents.

The addition of

N 2 O to these dosages will reduce systolic blood pressure.

At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated.

Dosages of to 30 mcg/kg have been shown to block sympathetic response including catecholamine release.

High doses are indicated in patients undergoing major surgical procedures, in which endotracheal intubation and mechanical ventilation are required, such as cardiovascular surgery and neurosurgery in the sitting position with maintenance of favorable myocardial and cerebral oxygen balance.

Postoperative observation is essential and postoperative mechanical ventilation may be required at the higher dosage range due to extended postoperative respiratory depression.

Depending on the initial dose, maintenance doses of 0.5 to 10 mcg/kg may be administered by slow injection in anticipation of surgical stress such as incision, sternotomy or cardiopulmonary bypass.

Sufentanil citrate may be administered by continuous or intermittent infusion as needed in response to signs of lightening of anesthesia.

In the absence of lightening of anesthesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.

The maintenance infusion rate for sufentanil should be based upon the induction dose so that the total dose for the procedure does not exceed 30 mcg/kg. 2.3 Epidural Use in Labor and Delivery Proper placement of the needle or catheter in the epidural space should be verified before sufentanil citrate is injected to assure that unintentional intravascular or intrathecal administration does not occur.

Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea.

Unintentional intrathecal injection of the full sufentanil, bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery.

• Sufentanil should be administered by slow injection.

Respiration should be closely monitored following each administration of an epidural injection of sufentanil.

• If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications.

Dosage for Labor and

• 10 to 15 mcg administered with 10 mL bupivacaine 0.125% with or without epinephrine.

• Sufentanil and bupivacaine should be mixed together before administration.

• Doses can be repeated twice (for a total of three doses) at not less than one-hour intervals until delivery.

Injection, USP equivalent to 50 mcg/mL sufentanil is supplied in the following single-dose containers: Unit of Sale Concentration NDC 0409-3382-21 Carton of 10 Single-dose Fliptop Vials 50 mcg/mL NDC 0409-3382-22 Carton of 10 Single-dose Fliptop Vials 100 mcg/2 mL (50 mcg/mL) NDC 0409-3382-25 Carton of 10 Single-dose Fliptop Vials 250 mcg/5 mL (50 mcg/mL) Protect from light.

Retain in carton until time of use.

Store at 20°C to 25°C (68°F to 77°F).

Protect from light.

Retain in carton until time of use.

Store at 20°C to 25°C (68°F to 77°F).

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with Sufentanil Citrate

Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis.

Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose.

No malformations were observed in either rats or rabbits at doses below the human procedural dose.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.

Opioid analgesics, including Sufentanil Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery.

Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery.

In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume).

Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively).

No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid - and high-dose group).

Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or 0.9 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively).

Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group).

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54 times the human procedural dose of 30 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps.

Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/day based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21.

Sufentanil reduced birth weights in the mid.

• and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases.

The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children.

The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug.

Elderly patients (aged 65 years or older) may have increased sensitivity to sufentanil.

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of Sufentanil Citrate

Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.