SUBLIMAZE PRESERVATIVE FREE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SUBLIMAZE PRESERVATIVE FREE (SUBLIMAZE PRESERVATIVE FREE).
Fentanyl is a potent synthetic opioid agonist with primary action at the mu-opioid receptor. It induces analgesia, sedation, and respiratory depression by activating G-protein-coupled receptors that inhibit adenylyl cyclase, reduce cAMP production, and modulate ion channels (e.g., potassium efflux, calcium influx).
| Metabolism | Fentanyl is primarily metabolized via N-dealkylation to norfentanyl by CYP3A4 in the liver. Other minor pathways include hydroxylation and amide hydrolysis. Less than 7% of the dose is excreted unchanged in urine. Metabolites are inactive. |
| Excretion | Primarily renal: fentanyl and its metabolites are excreted in urine (~75%) and feces (~9%). Less than 10% excreted unchanged. |
| Half-life | Terminal elimination half-life is 3-7 hours (mean 4.5 h) after IV administration, but may be prolonged (up to 12-15 h) in elderly, hepatic impairment, or after prolonged infusion due to redistribution. |
| Protein binding | Approximately 80-85% bound to plasma proteins, primarily alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Vd is 3-5 L/kg (range 1.5-6 L/kg) indicating extensive tissue distribution. High Vd contributes to prolonged elimination after long infusions. |
| Bioavailability | Intravenous: 100%; Intramuscular: ~90%; Transdermal: ~50-90% (highly variable); Oral: ~50% (first-pass metabolism); Sublingual/buccal: ~50-90% (absorption depends on mucosal pH). |
| Onset of Action | Intravenous: almost immediate (1-2 minutes); Intramuscular: 7-15 minutes; Transdermal: 12-24 hours for steady state. |
| Duration of Action | Intravenous: 30-60 minutes after a single dose (analgesic); longer with higher doses or continuous infusion due to redistribution half-life of 1-2 hours. Respiratory depression may persist beyond analgesic effect. |
IV: 0.5-2 mcg/kg bolus, may repeat q2-4h; or 0.5-1 mcg/kg/h infusion; IM: 0.5-2 mcg/kg q1-2h prn.
| Dosage form | INJECTABLE |
| Renal impairment | GFR 30-59: No adjustment; GFR <30: Consider 50% dose reduction and monitor; Hemodialysis: No supplemental dose. |
| Liver impairment | Child-Pugh A: No adjustment; Child-Pugh B: Reduce dose by 50%; Child-Pugh C: Avoid use or reduce dose by 75%. |
| Pediatric use | IV/IM: 0.5-3 mcg/kg q1-2h; Continuous IV infusion: 0.3-1 mcg/kg/h; Neonates: 0.5-2 mcg/kg q2-4h; Titrate to effect. |
| Geriatric use | Initial dose: 0.5 mcg/kg IV/IM; reduce by 50% of usual dose; titrate slowly due to increased sensitivity and prolonged half-life. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SUBLIMAZE PRESERVATIVE FREE (SUBLIMAZE PRESERVATIVE FREE).
| Breastfeeding | Fentanyl is excreted into breast milk in low concentrations. Milk-to-plasma ratio is approximately 2.86. The relative infant dose is less than 4% of the maternal weight-adjusted dose. Caution is advised, especially with repeated doses, due to potential for neonatal opioid effects. Monitor infant for drowsiness and respiratory depression. |
| Teratogenic Risk | FDA Pregnancy Category C. Fentanyl crosses the placenta. First trimester: Limited human data, animal studies show embryotoxicity and teratogenicity at high doses. Second and third trimesters: Chronic use may lead to fetal dependence and neonatal withdrawal syndrome. Use only if maternal benefit outweighs risk. |
■ FDA Black Box Warning
SUBLIMAZE PRESERVATIVE FREE is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid agonists. Serious, life-threatening, or fatal respiratory depression may occur. Monitor for respiratory depression, especially during initiation or following a dose increase. Accidental ingestion, especially by children, can result in a fatal overdose. Concomitant use with central nervous system (CNS) depressants, including other opioids, benzodiazepines, or ethanol, may produce profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate and limit dosages and durations to the minimum required. Neonatal opioid withdrawal syndrome (NOWS) may occur with prolonged use during pregnancy.
| Serious Effects |
["Hypersensitivity to fentanyl or any component of the formulation","Significant respiratory depression (in unmonitored settings or absence of resuscitative equipment)","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Paralytic ileus","Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy","Use in patients who have received MAOIs within the previous 14 days"]
| Precautions | ["Respiratory depression: Life-threatening; monitor oxygenation and ventilation, especially during initiation and dose escalation","Opioid-induced hyperalgesia: Consider dose reduction or opioid rotation if suspected","Serotonin syndrome: Risk when used concomitantly with serotonergic drugs","Adrenal insufficiency: Monitor for symptoms such as nausea, vomiting, anorexia, fatigue","Severe hypotension: Risk in patients with compromised ability to maintain blood pressure","Risks of use in patients with head injury or increased intracranial pressure: May obscure neurologic assessment","Risks of use in patients with chronic pulmonary disease: Avoid use or use with extreme caution","Risks of use in patients with biliary tract disease: May cause spasm of the sphincter of Oddi","Risks of use in patients with pancreatitis: May exacerbate symptoms","Risks of use in patients with impaired renal or hepatic function: Monitor closely for respiratory and CNS depression","Opioid withdrawal syndrome: Avoid abrupt discontinuation; taper dose gradually","Risks of driving and operating machinery: Impairment may persist despite feeling alert"] |
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| Fetal Monitoring | Monitor maternal respiratory rate, oxygen saturation, heart rate, and level of consciousness. Fetal heart rate monitoring is recommended during labor. Assess for neonatal respiratory depression and withdrawal symptoms post-delivery with prolonged use. |
| Fertility Effects | No well-controlled human studies. Animal studies indicate that fentanyl may impair fertility in males and females at high doses. Prolonged use may affect reproductive function, but reversibility is expected upon discontinuation. |