DURAGESIC-37
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DURAGESIC-37 (DURAGESIC-37).
Fentanyl binds to mu-opioid receptors, activating G-protein coupled receptor signaling, leading to inhibition of adenylate cyclase, decreased cAMP production, and modulation of ion channels (increased potassium efflux, decreased calcium influx). This results in reduced neuronal excitability, inhibition of nociceptive transmission, and altered pain perception. Additionally, fentanyl may interact with other opioid receptors (kappa, delta) with lower affinity.
| Metabolism | Fentanyl undergoes N-dealkylation and hydroxylation predominantly via hepatic CYP3A4 isoenzymes. Major metabolites include norfentanyl (inactive) and despropionylfentanyl (hydroxyfentanyl, inactive). Minor pathways involve CYP3A5 and possibly CYP2D6. Less than 10% of fentanyl is excreted unchanged in urine; most is eliminated as metabolites in urine and bile. |
| Excretion | Primarily renal: 75% as metabolites (mostly norfentanyl) and <10% unchanged drug. Fecal: 9% via biliary elimination. |
| Half-life | Terminal elimination half-life 20-27 hours (range 13-42 h) after transdermal removal; due to continuous absorption from skin depot, effective half-life is longer during patch wear. |
| Protein binding | Approximately 40% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 6 L/kg (range 4-7 L/kg), indicating extensive tissue distribution including brain and muscle. |
| Bioavailability | Transdermal: approximately 92% of the dose reaches systemic circulation due to high permeability and first-pass avoidance. |
| Onset of Action | Transdermal: 12-24 hours to steady state with first patch; initial analgesic effect may be delayed, requiring titration. |
| Duration of Action | 72 hours per patch; after removal, serum concentrations decline gradually (by ~50% in 20-27 h), providing residual analgesia for up to 12-24 hours. |
Initial: 25 mcg/hour transdermal patch applied every 72 hours. Titrate based on opioid tolerance. For opioid-naive patients: 12 mcg/hour patch.
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | eGFR 30-89 mL/min: no initial dose adjustment but monitor closely; eGFR <30 mL/min: reduce starting dose by 50% or use 12 mcg/hour patch and titrate cautiously. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce starting dose by 50%; Child-Pugh C: consider alternative therapy; if used, start with 12 mcg/hour and monitor. |
| Pediatric use | For opioid-tolerant children ≥2 years: initiate with 25 mcg/hour patch if converting from ≥60 mg oral morphine equivalent. For opioid-naive children: not recommended. Dosing per weight: apply patch size based on prior opioid requirement (mcg/hour). |
| Geriatric use | In patients >65 years: reduce starting dose by 50% (e.g., 12 mcg/hour for opioid-tolerant) and titrate slowly due to increased sensitivity and reduced clearance. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DURAGESIC-37 (DURAGESIC-37).
| Breastfeeding | Fentanyl is excreted into breast milk; M/P ratio ~0.4-1.0. Relative infant dose ~2.5% of maternal weight-adjusted dose. Caution: potential for infant sedation, respiratory depression. Single doses acceptable; monitor infant for drowsiness. Chronic use not recommended due to accumulation. |
| Teratogenic Risk | FDA Pregnancy Category C for chronic use; Category D for prolonged use or high doses at term. First trimester: risk of congenital anomalies unclear; may be associated with neural tube defects (case reports). Second/third trimesters: chronic use may cause fetal dependence, withdrawal, or respiratory depression. Near term: high doses can cause neonatal respiratory depression; use not recommended. Avoid during labor. |
■ FDA Black Box Warning
FENTANYL EXPOSES USERS TO RISKS OF ADDICTION, ABUSE, AND MISUSE, WHICH CAN LEAD TO OVERDOSE AND DEATH. ASSESS EACH PATIENT’S RISK PRIOR TO PRESCRIBING. SERIOUS, LIFE-THREATENING, OR FATAL RESPIRATORY DEPRESSION MAY OCCUR WITH USE. MONITOR FOR RESPIRATORY DEPRESSION, ESPECIALLY DURING INITIATION OR FOLLOWING DOSE INCREASES. ACCIDENTAL EXPOSURE TO FENTANYL, ESPECIALLY IN CHILDREN, CAN RESULT IN FATAL OVERDOSE. CONCOMITANT USE OF CYP3A4 INHIBITORS MAY INCREASE FENTANYL PLASMA CONCENTRATIONS, POTENTIALLY RESULTING IN FATAL RESPIRATORY DEPRESSION. NEONATAL OPIOID WITHDRAWAL SYNDROME MAY OCCUR WITH PROLONGED USE DURING PREGNANCY. CYTOCHROME P450 3A4 INHIBITOR CONCOMITANT USE OR DISCONTINUATION OF CYP3A4 INDUCERS MAY RESULT IN FATAL OVERDOSE.
| Serious Effects |
["Hypersensitivity to fentanyl or any component of the formulation.","Significant respiratory depression (especially in unmonitored settings or absence of resuscitative equipment).","Acute or severe bronchial asthma in unmonitored settings.","Known or suspected gastrointestinal obstruction (including paralytic ileus).","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy.","Opioid-naive patients (for formulation with strength > 12 mcg/hour, such as DURAGESIC-37, which is contraindicated in opioid-naive patients; initiation should be in opioid-tolerant patients).","Acute pain, including postoperative pain (except for short-term use in controlled settings).","Mild intermittent pain that can be managed with non-opioid analgesics."]
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| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function. Fetal monitoring: nonstress test, biophysical profile in third trimester if chronic use. Neonatal: observe for signs of opioid withdrawal (e.g., irritability, poor feeding) for 48-72 hours post-delivery. Avoid use in pregnancy unless benefit outweighs risk. |
| Fertility Effects | Opioids may disrupt ovulatory cycles via GnRH suppression. Fentanyl can cause hyperprolactinemia, reducing gonadotropin release. Reversible upon discontinuation. No specific human data on fertility impairment; potential for decreased fertility. |
| Precautions |
| ["Respiratory depression: Life-threatening; monitor closely, especially during initiation and dose titration.","Addiction, abuse, and misuse: Increased risk with high doses and prolonged use.","Neonatal opioid withdrawal syndrome: Occurs with prolonged use during pregnancy; monitor neonates.","Interactions with CNS depressants (e.g., alcohol, benzodiazepines): Additive respiratory depression; avoid or reduce doses.","CYP3A4 interactions: Co-administration with CYP3A4 inhibitors (e.g., macrolides, azole antifungals) can increase fentanyl exposure; discontinue or reduce fentanyl dose. Co-administration with CYP3A4 inducers (e.g., rifampin, carbamazepine) may decrease efficacy.","Use in elderly or debilitated patients: Increased risk of respiratory depression; start with low doses and titrate slowly.","Use in patients with chronic pulmonary disease (e.g., COPD, cor pulmonale): Monitor respiratory function; may cause significant respiratory depression.","Use in patients with hepatic or renal impairment: Altered pharmacokinetics; monitor for adverse effects.","Use in patients with head injury or increased intracranial pressure: Avoid due to potential for respiratory depression and elevated CSF pressure; fentanyl may obscure neurological signs.","Use in patients with bradyarrhythmias (e.g., bradycardia): Fentanyl can decrease heart rate; use with caution.","Use in patients with convulsive disorders: May worsen seizures; monitor.","Use in patients with opioid addiction: May precipitate withdrawal; use only in opioid-tolerant patients.","Abrupt discontinuation: Can cause withdrawal symptoms; taper gradually.","Risk of severe hypotension: Especially in hypovolemic patients or those with compromised cardiovascular function.","Serotonin syndrome: Risk with concomitant use of serotonergic drugs (e.g., SSRIs, MAOIs); monitor for symptoms.","Adrenal insufficiency: Possible with prolonged opioid use; evaluate if symptoms develop.","Androgen deficiency: Possible with long-term use; consider if symptoms such as decreased libido, impotence, or amenorrhea occur.","Acute abdominal conditions: May obscure diagnosis or clinical course."] |