리미펜타닐

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Remifentanil hydrochloride/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Remifentanil hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Remifentanil hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Remifentanil hydrochloride/

ACCIDENTAL RELEASE MEASURES: Avoid dust formation. Avoid breathing vapors, mist or gas. Evacuate personnel to safe areas. Environmental precautions: Do not let product enter drains. /Remifentanil hydrochloride/

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Remifentanil hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Remifentanil hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Remifentanil hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Remifentanil hydrochloride/

Skin protection: Handle with gloves. /Remifentanil hydrochloride/

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Remifentanil hydrochloride/

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Remifentanil hydrochloride/

A patient who manifested signs of serotonin syndrome during an intravenous anesthetic with remifentanil and propofol is presented. The patient displayed lower extremity clonus, nystagmus, and diaphoresis. At the time of surgery, the patient was being treated with fluoxetine (a selective serotonin reuptake inhibitor). A presumptive diagnosis of serotonin syndrome was made intraoperatively and all opioids were discontinued. His symptoms resolved in the Postanesthesia Care Unit without incident.

Comprehensive strategies for the treatment of colorectal cancer (CRC) have become increasingly important. One of the most important factors is pain relief. Therefore, patients with CRC are concurrently treated with analgesics and chemotherapeutic agents; however, the effects of analgesics on the therapeutic activity of chemotherapeutic agents remain largely unknown. The present study investigated the effects of three widely used analgesics in clinics: Fentanyl, remifentanil and sufentanil, on the cytotoxicity of oxaliplatin, a commonly used chemotherapeutic agent for CRC. Furthermore, the underlying mechanisms of those effects in association with connexin 43 (Cx43)-composed gap junction (GJ) function were analyzed. The Lovo, Colo320, HCT116 and HT29 human CRC cell lines, with or without Cx43 expression, were used to examine the effects of the three analgesics on the cytotoxicity of oxaliplatin. The results demonstrated that in the cell lines expressing Cx43 (Lovo and Colo320), the cytotoxicity of oxaliplatin was attenuated and Cx43 GJ function was inhibited. Sufentanil, not fentanyl or remifentanil, inhibited Cx43 GJ function effectively, and reduced the cytotoxicity of oxaliplatin. In contrast, these effects were not observed in the other two colon cancer cell lines not expressing Cx43 (HCT116 and HT29). These results suggested that alternation of Cx43 GJ function may regulate the cytotoxicity of oxaliplatin in regard to CRC. Furthermore, sufentanil, not fentanyl or remifentanil, suppressed the cytotoxicity of oxaliplatin through inhibition of Cx43 GJ function. These results may be beneficial for the treatment of CRC and reduction of treatment resistance.

Serotonin syndrome may occur in patients receiving opiate agonists concomitantly with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans"), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT3 receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort (Hypericum perforatum), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline). Serotonin syndrome may occur within the recommended dosage ranges for these drugs. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. If concomitant use of other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases. If serotonin syndrome is suspected, treatment with remifentanil, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.

Table: Clinically Significant Drug Interactions with Ultiva [Table#8414]

For more Interactions (Complete) data for Remifentanil (12 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a structure estimation method(2), indicates that remifentanil is expected have moderate mobility in soil(SRC). The estimated pKa of remifentanil is 7.51(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation form from moist soil is not expected because cations do not volatilize(SRC). Volatilization of neutral remifentanil from moist soil surfaces is not expected(SRC) given an estimated Henry's Law constant of 1.3X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Remifentanil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a structure estimation method(2), indicates that remifentanil is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 7.51(3) indicates remifentanil will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization of the cation from water surfaces is not expected to be an important fate process(SRC). Volatilization from water surfaces of neutral remifentanil is not expected(4) based upon an estimated Henry's Law constant of 1.3X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). The estimated hydrolysis half-life of remifentanil at pH values of 7 and 8 was calculated as 3.2 years and 118 days, respectively(2). According to a classification scheme(5), an estimated BCF of 4(SRC), from an estimated log Kow of 1.45(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2017).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), remifentanil, which has an estimated vapor pressure of 1.2X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase remifentanil may be removed from the air by wet and dry deposition(SRC). Remifentanil contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Remifentanil is an oil. It is a Schedule II Controlled Substance. It is approved in the US for intravenous administration as an analgesic agent for use during the induction and maintenance of general anesthesia. Remifentanil is also used as an anesthetic agent in animals. HUMAN STUDIES: Remifentanil is a selective mu-receptor agonist with similar potency to fentanyl; the drug shares the actions of the opiate agonists. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of the drug, the risk is greatest during the initiation of therapy or following a dosage increase. Acute overdose 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use with serotonergic drugs. Remifentanil, like other opioids, has a high potential for abuse. ANIMAL STUDIES: The fertility of female rats was not affected at IV doses as high as 1 mg/kg, when administered for at least 15 days before mating. In another study, reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity. Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day. No malformations were reported in surviving fetuses despite clear maternal toxicity. However, remifentanil has been shown to reduce fertility in male rats when tested after 70+ days of daily IV administration of 0.5 mg/kg. Remifentanil was not genotoxic in an Ames test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels >/= 308 ug/mL only in the presence of metabolic activation.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of remifentanil can be estimated to be 230(SRC). According to a classification scheme(2), this estimated Koc value suggests that remifentanil is expected to have moderate mobility in soil. The estimated pKa of remifentanil is 7.51(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously. In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PET(CO2)) at approximately 46 or 56 mm Hg (alternate subjects). After 6 min of equilibration, subjects received 0.5 microg/kg remifentanil over 5 s, and minute ventilation (V(E)) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mm Hg). The V(E) data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (k(eo)), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve (gamma). The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 L/min/ mm Hg [-0.12 to 0.66] 2 min after remifentanil (P<0.001); within 5 min, it recovered to approximately 0.6 L/min/mm Hg, and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mm Hg (VE50) decreased from 12.9 [9.8 to 15.9] to 6.1 L/min [4.8 to 7.4] 2.5 min after remifentanil injection (P<0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of VE50 included k(eo) = 0.24 min(-1) (T1/2 = 2.9 min), EC50 = 1.12 ng/mL, and gamma = 1.74. After administration of 0.5 ug/kg remifentanil, there was a decrease in slope and downward shift of the carbon dioxide ventilatory response curve. This reached its nadir approximately 2.5 min after injection, consistent with the computed onset half-time of 2.9 min. The onset of respiratory depression appears to be somewhat slower than previously reported for the onset of remifentanil-induced electroencephalographic slowing. Recovery of ventilatory drive after a small dose essentially was complete within 15 min.

/HUMAN EXPOSURE STUDIES/ Hyperoxemia depresses the output of peripheral and central chemoreceptors. Patients treated with opioids often receive supplemental oxygen to avert possible decreases in oxygen saturation (Sp(O2)).We examined the effect of a single dose of remifentanil in healthy volunteers inhaling room air vs air enriched with 50% oxygen. Twenty healthy volunteers received i.v. 50 mg remifentanil (infused over 60 s) at normoxic (N) or hyperoxic (FI(O2) 0.5, H) background on separate occasions. Minute ventilation (Vi), respiratory rate (RR), end-tidal PC(O2), and Sp(O2) were collected on a breath to-breath basis. The occurrence of apnea was recorded. During normoxia, remifentanil decreased Vi from 7.4 (1.3) [mean (SD)] to 2.2 (1.2) liter min 21 (P,0.01), and during hyperoxia from 7.9 (1.0) to 1.2 (1.2) liter min 21 (P,0.01; H vs N: P,0.001). RR decreased from 13.1 (2.9) to 6.1 (2.8) bpm during N (P,0.01) and from 13.2 (3.0) to 3.6 (4.0) bpm during H (P,0.01; H vs N: P,0.01). During normoxia, Sp(O2) decreased from 98.4 (1.5) to 88.6 (6.7)% (P,0.01), while during hyperoxia, Sp(O2) changed from 99.7 (0.7) to 98.7 (1.0)% (P,0.001). Apnea developed in two subjects during normoxia and 10 during hyperoxia. Respiratory depression from remifentanil is more pronounced in hyperoxia than normoxia as determined from minute ventilation, end-tidal PC(O2), and RR. During hyperoxia, respiratory depression may be masked when measuring Sp(O2) as pulse oximetry remains in normal values during the first minutes of respiratory depression.

Remifentanil's production and administration as an analgesic and anesthetic adjunct in humans(1) and animals(2) may result in its release to the environment through various waste streams(SRC). It is a Schedule II controlled substance(3).[(1) National Library of Medicine. PubMed Health. Available from, as of May 8, 2017: https://www.ncbi.nlm.nih.gov/pubmedhealth/ (2) Papich MG; Saunders Handbook of Veterinary Drugs Small and Large Animal. 3rd ed. St. Louis, MO: Elsevier Saunders, p. 681 (2011) (3) DEA; Title 21 Code Fed Reg. Part 1308 - Schedules of Controlled Substances. Schedules. Sec 1308.12 Schedule II.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

remifentanil

DILI Positive

Intravenous

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 4 was calculated in fish for remifentanil(SRC), using an estimated log Kow of 1.45(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low.

An estimated pKa of 7.51(1) indicates remifentanil will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization of the cation from water and moist soil surfaces is not expected to be an important fate process(SRC). The Henry's Law constant for remifentanil is estimated as 1.3X10-14 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that neutral remifentanil is expected to be essentially nonvolatile from water and moist soil surfaces(3). Remifentanil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-8 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Acute Exposure/ The efficacy of opioid administration to reduce postoperative pain is limited by respiratory depression. We investigated whether clinically relevant opioid concentrations altered the respiratory pattern in the parabrachial nucleus, a pontine region contributing to respiratory pattern generation, and compared these effects with a medullary respiratory site, the pre-Botzinger complex. Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjections elicited tachypnea. Two protocols were performed in separate sets of animals. First, bilateral microinjections of the mu-opioid receptor agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (100 uM) into the "tachypneic area" determined the effect of maximal mu-opioid receptor activation. Second, respiratory rate was decreased with continuous IV infusions of remifentanil. The opioid antagonist naloxone (1 mM) was then microinjected bilaterally into the "tachypneic area" of the parabrachial nucleus to determine whether the respiratory rate depression could be locally reversed. Average respiratory rate was 27 +/- 10 breaths/min. First, [D-Ala, N-MePhe, Gly-ol]-enkephalin injections decreased respiratory rate by 62 +/- 20% in young and 45 +/- 26% in adult rabbits (both P < 0.001). Second, during IV remifentanil infusion, bilateral naloxone injections into the "tachypneic area" of the parabrachial nucleus reversed respiratory rate depression from 55 +/- 9% to 20 +/- 14% in young and from 46 +/- 20% to 18 +/- 27% in adult rabbits (both P < 0.001). The effects of bilateral [D-Ala, N-MePhe, Gly-ol]-enkephalin injection and IV remifentanil on respiratory phase duration in the "tachypneic area" of the parabrachial nucleus was significantly different from the pre-Botzinger complex. The "tachypneic area" of the parabrachial nucleus is highly sensitive to mu-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The fertility of female rats was not affected at IV doses as high as 1 mg/kg which is 0.4 times a human intravenous infusion of an induction dose of 1 ug/kg with a maintenance dose of 2 ug/kg/min in terms of mg/sq m of body surface area for a surgical procedure lasting 3 hours or approximately 80 times a single bolus human dose of 2 ug/kg, in terms of mg/sq m of body surface area, when administered for at least 15 days before mating.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant rats were treated from Gestation Day 6 to Lactation Day 21 with intravenous boluses of remifentanil 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 ug/kg with a maintenance dose of 2 ug/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity (increased mortality in all groups).

The remifentanil in Ultiva may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Ultiva may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Ultiva. Opioids may also obscure the clinical course in a patient with a head injury.

The remifentanil in Ultiva may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Ultiva therapy.

As for all potent opioids, caution is required with use in morbidly obese patients because of alterations in cardiovascular and respiratory physiology.

For more Populations at Special Risk (Complete) data for Remifentanil (10 total), please visit the HSDB record page.

A base-catalyzed second-order hydrolysis rate constant of 0.068 L/mole-sec(SRC) was estimated for remifentanil using a structure estimation method(1); this corresponds to half-lives of 3.2 years and 118 days at pH values of 7 and 8, respectively(1). Remifentanil contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including remifentanil hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Remifentanil hydrochloride/

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted:. Remifentanil (DEA Code Number: 9739) is included on this list.

Remifentanil (DEA Code Number: 9739) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Analgesics, Opioid; Hypnotics and Sedatives; Anesthetics, Intravenous

MEDICATION

Preparation: P.L. Feldman et al., European Patent Office patent 383579; eidem, United States of America patent 5019583 (1990, 1991 both to Glaxo)

Remifentanil is prepared by condensation of methyl 4-(phenylpropionylamino)piperidine-4-carboxylate with methyl acrylate in hot acetonitrile.

Ultiva (remifentanil hydrochloride) for Injection, for intravenous use, is supplied as follows: 3 mL vial (concentration: 1 mg lyophilized power); 5 mL vial (concentration: 2 mg lyophilized power); 10 mL vial (concentration: 5 mg lyophilized power).