Remifentanil

Black Box Warnings

Addiction, abuse, and misuse

• Therapy exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death
• Assess each patient’s risk prior to prescribing therapy, and monitor all patients regularly for the development of these behaviors and conditions

Contraindications

Epidural or intrathecal administration

Known hypersensitivity to fentanyl analogs

Cautions

In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate

Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

Muscle rigidity occurring during induction of can be treated by decreasing rate or discontinuing infusion of drug or by administering a neuromuscular blocking agent; neuromuscular blocking agents used should be compatible with patient's cardiovascular status

Bradycardia may occur; monitor heart rate during dosage initiation and titration; responsive to ephedrine or anticholinergic drugs

Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

Not to be administered into same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products

Therapy may increase frequency of seizures in patients with seizure disorders and in other clinical settings associated with seizures; monitor patients for worsened seizure control during therapy

May cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; monitor closely

Continuous infusions should be administered only by an infusion device

Clear IV tubing after discontinuation of remifentanil

May be associated with apnea and respiratory depression, skeletal muscle rigidity

Should not be administered in same IV tubing as blood

Intraoperative awareness in some pts under 55 yo when admin. with propofol infusion < 75 mcg/kg/min

ULTIVA is indicated for intravenous (IV) administration:

• As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
• For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.
• As an analgesic component of monitored anesthesia care in adult patients.

Remifentanil is a narcotic (opioid) pain medicine.

Remifentanil is used to treat or prevent acute pain after surgery.

Remifentanil may be used for other purposes not listed in this medication guide.

Remifentanil can cause side effects that may impair your thinking or reactions. You should not plan on driving or doing anything that requires you to be awake and alert right after you are treated with this medication.

Follow your doctor's instructions about any other restrictions on food, beverages, or activity after you are treated with remifentanil.

Take remifentanil exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The Remifentanil dose your doctor recommends will be based on the following (use any or all that apply):

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Remifentanil is available in the following doses:

• Remifentanil 1 Mg Intravenous Powder For Injection
• Remifentanil 2 Mg Intravenous Powder For Injection
• Remifentanil 5 Mg Intravenous Powder For Injection

Usual Adult Dose for Anesthesia:

INDUCTION of Anesthesia (through intubation): 0.5 to 1 mcg/kg/min via continuous IV infusion; an initial dose of 1 mcg/kg over 30 to 60 seconds may be administered
-If endotracheal intubation is to occur less than 8 minutes after start of the induction infusion, an initial IV dose should be given
MAINTENANCE of Anesthesia:
-With Nitrous Oxide at 66%: Continuous IV infusion at 0.4 mcg/kg/min (range 0.1 to 2 mcg/kg/min)
-With Isoflurane at 0.4 to 1.5 MAC or Propofol at 100 to 200 mcg/kg/min: Continuous IV infusion at 0.25 mcg/kg/min (range 0.05 to 2 mcg/kg/min)
-An IV bolus of 1 mcg/kg over 30 to 60 seconds may be used every 2 to 5 minutes as needed in response to light anesthesia or transient episodes of intense surgical stress
POSTOPERATIVE: Bolus IV injections are not recommended
-Use continuous IV infusion at 0.1 mcg/kg/min; adjust infusion rate every 5 minutes in 0.025 mcg/kg/min increments to balance level of analgesia and respiratory rate
Maximum rate: 0.2 mcg/kg/min

MONITORED ANESTHESIA CARE (MAC): Supplemental oxygen should be supplied
IV BOLUS Doses: Give 90 seconds before local anesthetic
-With midazolam 2 mg: Administer 0.5 mcg/kg IV over 30 to 60 seconds
-Without midazolam: Administer 1 mcg/kg IV over 30 to 60 seconds
CONTINUOUS IV Infusion: Start infusion 5 minutes before local anesthetic
-With midazolam 2 mg: Initiate at 0.05 mcg/kg/min, then after local anesthetic decrease to 0.025 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min)
-Without midazolam: Initiate IV infusion at 0.1 mcg/kg/min, then after local anesthetic decrease to 0.05 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min)

Comments:
-Dosing should be individualized based on response.
-Monitor patients closely for respiratory depression, especially with initiation and following all dose increases; adjust dose accordingly
-Continuous IV infusions should be administered by a calibrated infusion device.
-Due to rapid offset of action, no residual analgesic activity will be present 5 to 10 minutes after discontinuation; if pain is expected, alternative analgesics should be administered prior to discontinuing.

Uses: As an analgesic during induction and maintenance of general anesthesia; for continuation of analgesia into the immediate postoperative period; and as an analgesic component of monitored anesthesia.

Usual Adult Dose for Pain:

INDUCTION of Anesthesia (through intubation): 0.5 to 1 mcg/kg/min via continuous IV infusion; an initial dose of 1 mcg/kg over 30 to 60 seconds may be administered
-If endotracheal intubation is to occur less than 8 minutes after start of the induction infusion, an initial IV dose should be given
MAINTENANCE of Anesthesia:
-With Nitrous Oxide at 66%: Continuous IV infusion at 0.4 mcg/kg/min (range 0.1 to 2 mcg/kg/min)
-With Isoflurane at 0.4 to 1.5 MAC or Propofol at 100 to 200 mcg/kg/min: Continuous IV infusion at 0.25 mcg/kg/min (range 0.05 to 2 mcg/kg/min)
-An IV bolus of 1 mcg/kg over 30 to 60 seconds may be used every 2 to 5 minutes as needed in response to light anesthesia or transient episodes of intense surgical stress
POSTOPERATIVE: Bolus IV injections are not recommended
-Use continuous IV infusion at 0.1 mcg/kg/min; adjust infusion rate every 5 minutes in 0.025 mcg/kg/min increments to balance level of analgesia and respiratory rate
Maximum rate: 0.2 mcg/kg/min

MONITORED ANESTHESIA CARE (MAC): Supplemental oxygen should be supplied
IV BOLUS Doses: Give 90 seconds before local anesthetic
-With midazolam 2 mg: Administer 0.5 mcg/kg IV over 30 to 60 seconds
-Without midazolam: Administer 1 mcg/kg IV over 30 to 60 seconds
CONTINUOUS IV Infusion: Start infusion 5 minutes before local anesthetic
-With midazolam 2 mg: Initiate at 0.05 mcg/kg/min, then after local anesthetic decrease to 0.025 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min)
-Without midazolam: Initiate IV infusion at 0.1 mcg/kg/min, then after local anesthetic decrease to 0.05 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min)

Comments:
-Dosing should be individualized based on response.
-Monitor patients closely for respiratory depression, especially with initiation and following all dose increases; adjust dose accordingly
-Continuous IV infusions should be administered by a calibrated infusion device.
-Due to rapid offset of action, no residual analgesic activity will be present 5 to 10 minutes after discontinuation; if pain is expected, alternative analgesics should be administered prior to discontinuing.

Uses: As an analgesic during induction and maintenance of general anesthesia; for continuation of analgesia into the immediate postoperative period; and as an analgesic component of monitored anesthesia.

Usual Geriatric Dose for Anesthesia:

Reduce initial adult dose by 50%
-Titrate dose cautiously to effect

Usual Geriatric Dose for Pain:

Reduce initial adult dose by 50%
-Titrate dose cautiously to effect

Usual Pediatric Dose for Anesthesia:

Birth to 2 months old:
-Continuous IV Infusion (with 70% nitrous oxide): 0.4 mcg/kg/min (range 0.4 to 1 mcg/kg/min)
-Supplemental IV bolus of 1 mcg/kg every 2 to 5 minutes may be given in response to light anesthesia or transient episodes of intense surgical stress

1 to 12 years:
MAINTENANCE of Anesthesia:
-IV Bolus: Initial dose of 1 mcg/kg may be administered over 30 to 60 seconds
-Continuous IV Infusion (concomitant administration with Halothane [0.3 to 1.5 MAC], Sevoflurane [0.3 to 1.5 MAC], or Isoflurane [0.4 to 1.5 MAC]): 0.25 mcg/kg/min (range 0.05 to 1.3 mcg/kg/min)
-Supplemental IV bolus of 1 mcg/kg every 2 to 5 minutes may be given in response to light anesthesia or transient episodes of intense surgical stress

Comments:
-Drug clearance in neonates is highly variable (on average 2 times higher than young, healthy adults, therefore, increased infusion rates or supplemental IV bolus doses may be needed in these patients.
-In neonates with significant co-morbidities, those undoing significant fluid shifts, those who have not been pretreated with atropine, or those receiving potent inhalation agents or neuraxial anesthesia, smaller IV bolus doses should be considered to avoid hypotension and/or bradycardia.
-Due to rapid offset of action, no residual analgesic activity will be present 5 to 10 minutes after discontinuation; if pain is expected, alternative analgesics should be administered prior to discontinuation.
-This drug has not been studied in patients under 12 years of age for use in the immediate postoperative period or for use as a component of monitored anesthesia care.

Use: As an analgesic agent during maintenance of general anesthesia.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• Avoid drinking alcohol for 24 hours after surgery.
• This medicine may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking remifentanil.
• This medicine has an opioid drug in it. The use of opioid drugs along with a benzodiazepine drug or other drugs that may make you drowsy or slow your actions has led to very bad side effects. Side effects that have happened include slowed or trouble breathing and deaths. Benzodiazepine drugs include drugs like alprazolam, diazepam, and lorazepam. Benzodiazepine drugs are used to treat many health problems like anxiety, trouble sleeping, or seizures. Talk with the doctor.
• Many drugs interact with this medicine and can raise the chance of side effects like deadly breathing problems. Talk with your doctor and pharmacist to make sure it is safe to use remifentanil with all of your drugs.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using remifentanil while you are pregnant.
• Using this medicine for a long time during pregnancy may lead to withdrawal in the newborn baby. This can be life-threatening. Talk with the doctor.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Ultiva: 1 mg (1 ea); 2 mg (1 ea); 5 mg (1 ea)

IV: 1 to 3 minutes; Peak effect: 3 to 5 minutes

Time to Peak

Intranasal: Children ≤7 years: ~3.5 minutes (Verghese 2008)

There are no dosage adjustments provided in the manufacturer's labeling; however, remifentanil pharmacokinetics are unchanged in patients with severe hepatic impairment.

Frequency of adverse events may vary based on surgical procedures and rate of infusion.

>10%:

Cardiovascular: Hypotension (2% to 19%)

Central nervous system: Headache (<2% to 18%)

Dermatologic: Pruritus (<2% to 18%)

Gastrointestinal: Nausea (<36% to 44%), vomiting (<16% to 22%)

Neuromuscular & skeletal: Muscle rigidity (≤11%; includes chest wall rigidity)

1% to 10%:

Cardiovascular: Bradycardia (1% to 7%; dose-dependent), shivering (<5%), hypertension (1% to 2%; dose-dependent), flushing (1%), flushing sensation (1%), tachycardia (≤1%; dose-dependent)

Central nervous system: Dizziness (<5%), chills (1%), agitation (≤1%)

Dermatologic: Diaphoresis (6%)

Local: Pain at injection site (1%)

Respiratory: Respiratory depression (<7%), apnea (<3%), hypoxia (≤1%)

Miscellaneous: Fever (<5%), postoperative pain (<2%)

Rare but important or life-threatening: Abdominal distress, amnesia, anaphylaxis, anxiety, awareness under anesthesia without pain, bronchitis, bronchospasm, cardiac arrhythmia, chest pain, confusion, constipation, cough, diarrhea, disorientation, disruption of body temperature regulation, dysphagia, dysphoria, dyspnea, dysuria, ECG changes, electrolyte disturbance, erythema, gastroesophageal reflux disease, hallucination, heart block, heartburn, hepatic insufficiency, hiccups, hyperglycemia, increased creatine phosphokinase, intestinal obstruction, involuntary body movements, laryngospasm, leukocytosis, lymphocytopenia, nasal congestion, nightmares, nystagmus, oliguria, paresthesia, pharyngitis, pleural effusion, prolonged emergence from anesthesia, pulmonary edema, rales, rapid awakening from anesthesia, rhinorrhea, rhonchi, seizure, skin rash, sleep disorder, stridor, syncope, thrombocytopenia, tremor, twitching, urinary incontinence, urinary retention, urticaria, xerostomia

Respiratory and cardiovascular status, blood pressure, heart rate

No adjustment recommended

No adjustment recommended

Data not available

Benefit should outweigh risk AU TGA pregnancy category: C US FDA pregnancy category: Not Assigned Risk Summary: Available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage; prolonged use during pregnancy may cause neonatal opioid withdrawal syndrome. Comments: -Neonates exposed to opioid analgesics during labor should be monitored for signs of excess sedation and respiratory depression. -Prolonged maternal use of opioids during pregnancy can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Reduced fetal rat body weight and pup weights have been reported at 2.2 times the human doses; no malformations were observed with bolus injections to pregnant rats or rabbits during organogenesis at doses up to 5 times human doses. This drug rapidly crosses the placenta and may produce respiratory depression in the neonate; IV use is generally not recommended during or immediately prior to labor when other analgesic techniques are more appropriate. As with other narcotics, opioid effects can be quickly reversed with naloxone. There are no adequate and well controlled studies in pregnant women. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Summary of Use during Lactation

Because the half-life of remifentanil is extremely short, it is unlikely to cause any adverse effects in the breastfed newborn if it is given to the mother for labor analgesia or a surgical procedure. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of remifentanil to a few days. However, because no information is available on the use of remifentanil during breastfeeding, an alternate drug may be preferred if the mother requires prolonged administration of remifentanil during the early postpartum period. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately.

Drug Levels

Remifentanil is administered intravenously and has a half-life of about 3 minutes in adults. Its oral bioavailability is unknown.

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Four mothers who were breastfeeding their infants received remifentanil as part of their general anesthesia for surgical procedures. All patients also receved intravenous propofol and rocuronium, and inhaled xenon as part of the anesthesia. They were given doses of remifentanil that targeted a serum concentration of 4.5 mcg/L during the procedure and reduced to achieve a target concentration of 1.5 mcg/L at the end of anesthesia. Individual infants were first breastfed as follows: 1.5 hours, 2.8 hours, 4.6 hours, and 5 hours after extubation. No signs of sedation were observed in any of the infants.[1]

Effects on Lactation and Breastmilk

Narcotics can increase serum prolactin.[2][3] However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

A double-blind, randomized study compared patient-controlled intravenous (IV) analgesia with remifentanil (n = 43) to a continuous meperidine infusion (n = 45) for labor analgesia. Patients receiving remifentanil used an average total dosage of 1035 mcg/kg and those receiving meperidine received an average total dosage of 150 mg/kg. Breastfeeding difficulties were experienced in 6.3% of the infants of mothers who received remifentanil and 12.8% of infants whose mothers received meperidine; however, this difference was not statistically significant.[4]

Alternate Drugs to Consider

Acetaminophen, Butorphanol, Fentanyl, Hydromorphone, Ibuprofen, Morphine

References

1. Stuttmann R, Schafer C, Hilbert P et al. The breast feeding mother and xenon anaesthesia: Four case reports. Breast feeding and xenon anaesthesia. BMC Anesthesiol. 2010;10:1. PMID: 20167123

2. Tolis G, Dent R, Guyda H. Opiates, prolactin, and the dopamine receptor. J Clin Endocrinol Metab. 1978;47:200-3. PMID: 263291

3. Frecska E, Perenyi A, Arato M. Blunted prolactin response to fentanyl in depression. Normalizing effect of partial sleep deprivation. Psychiatry Res. 2003;118:155-64. PMID: 12798980

4. Evron S, Glezerman M, Sadan O et al. Remifentanil: a novel systemic analgesic for labor pain. Anesth Analg. 2005;100:233-8. PMID: 15616083