FENTORA
Clinical safety rating
cautionComprehensive clinical and safety monograph for FENTORA (FENTORA).
Fentanyl is a potent mu-opioid receptor agonist, binding to and activating opioid receptors in the brain and spinal cord, leading to analgesia and sedation.
| Metabolism | FENTORA is primarily metabolized by CYP3A4 to norfentanyl and other metabolites. |
| Excretion | Primarily renal: Approximately 75% of the dose is excreted in urine as metabolites (mostly norfentanyl, despropionylfentanyl, and hydroxyfentanyl), with less than 7% as unchanged fentanyl. Fecal elimination accounts for about 9%. |
| Half-life | Terminal elimination half-life is approximately 2–4 hours in adults, but can range from 2 to 6 hours depending on hepatic clearance. In elderly or hepatically impaired patients, half-life may be prolonged. The rapid initial decline is due to redistribution, and the terminal phase reflects slow elimination from deep compartments. |
| Protein binding | Approximately 80–85% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein (AAG). Binding is concentration-dependent and may decrease in conditions with low albumin or elevated AAG. |
| Volume of Distribution | Volume of distribution (Vd) is 3–6 L/kg, indicating extensive tissue distribution. Large Vd reflects high lipophilicity and rapid uptake into tissues such as fat and muscle, contributing to redistribution and prolonged effects with repeated doses. |
| Bioavailability | Buccal administration: Absolute bioavailability is approximately 65–70% due to first-pass metabolism and some swallowed drug. Sublingual delivery is similar, but variability is high. Compared to IV, buccal bioavailability is consistent at ~65%. |
| Onset of Action | Buccal administration: Onset of analgesia occurs within 15–30 minutes, with peak effect at 30–60 minutes. Transmucosal absorption is rapid, leading to early analgesic effects. |
| Duration of Action | Duration of action is 1–3 hours after a single buccal dose, corresponding to the time to return to baseline pain. Continuous use may lead to accumulation with prolonged terminal half-life. Clinical duration may be shorter due to redistribution. |
| Molecular Weight | 336.47 |
For opioid-tolerant adults: 100 mcg (one tablet) placed in buccal cavity; titrate upward in increments of 100 mcg per breakthrough pain episode, with minimum 2-hour interval between doses; maximum 4 doses per day.
| Dosage form | TABLET |
| Renal impairment | For GFR <30 mL/min: initiate at 50 mcg (half a 100 mcg tablet) and titrate cautiously; no specific adjustment for GFR 30-89 mL/min. |
| Liver impairment | Child-Pugh Class A or B: initiate at 50 mcg and titrate cautiously; Child-Pugh Class C: not recommended. |
| Pediatric use | Not approved for use in pediatric patients (safety and efficacy not established). |
| Geriatric use | Initiate at 50 mcg in patients aged ≥65 years and titrate cautiously; monitor for respiratory depression and cognitive impairment. |
| 1st trimester | Associated with congenital malformations; consider folic acid deficiency risk. |
| 2nd trimester | May cause fetal dependence and withdrawal; use only if clearly needed. |
| 3rd trimester | Risk of neonatal respiratory depression, opioid withdrawal syndrome. |
Clinical note
Comprehensive clinical and safety monograph for FENTORA (FENTORA).
| Placental transfer | Fentanyl readily crosses the placenta; detected in fetal circulation within 5 minutes of maternal administration. |
| Breastfeeding | Fentanyl is excreted in breast milk; monitor infant for sedation, respiratory depression, and withdrawal symptoms. Avoid use in breastfeeding due to potential for infant toxicity. |
| Lactation Rating | L4 (Hazardous) |
| Teratogenic Risk | Insufficient human data; animal studies show increased skeletal anomalies and reduced fetal weight at high doses. Fentanyl is not a major teratogen but chronic use may cause neonatal opioid withdrawal syndrome (NOWS) in third trimester. Avoid in pregnancy unless benefits outweigh risks. |
| Fetal Monitoring | Monitor maternal respiratory rate, oxygen saturation, and sedation level; fetal heart rate monitoring during labor; assess for neonatal respiratory depression and NOWS in newborns if used near delivery. |
| Fertility Effects | Animal studies show reduced fertility and implantation at high doses. Human data limited; chronic opioid use may disrupt menstrual cycle and fertility, but fentanyl's effect is not well studied. Use with caution in women attempting conception. |
■ FDA Black Box Warning
WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; RISK OF SEROTONIN SYNDROME; RISK OF ADRENAL INSUFFICIENCY; SEVERE HYPOTENSION; GASTROINTESTINAL ADVERSE REACTIONS; SEIZURES; AND INCREASED INTRACRANIAL PRESSURE, HEAD INJURY, OR IMPAIRED CONSCIOUSNESS.
| Serious Effects |
Hypersensitivity to fentanyl or any componentOpioid-naive patients (not for acute pain management)Significant respiratory depressionAcute or severe bronchial asthmaParalytic ileusConcurrent MAO inhibitors or within 14 daysManagement of acute or postoperative pain (not indicated)
| Precautions | Life-threatening respiratory depression, Addiction, abuse, and misuse, Risk of medication errors (dosing and product confusion), Accidental exposure (especially in children), Neonatal opioid withdrawal syndrome, Risks from concomitant use with benzodiazepines or other CNS depressants, Interaction with alcohol, Risk of serotonin syndrome, Risk of adrenal insufficiency, Severe hypotension, Gastrointestinal adverse reactions (e.g., constipation), Seizures, Increased intracranial pressure, Use in patients with head injury or impaired consciousness |
| Food/Dietary | Avoid grapefruit juice and grapefruit products as they inhibit CYP3A4 and can increase fentanyl levels, raising risk of respiratory depression and QT prolongation. Do not consume alcohol; additive CNS depression may occur. No other known significant food interactions; however, avoid high-fat meals immediately before or after administration as they may alter absorption. |
| Clinical Pearls | FENTORA (fentanyl buccal tablet) is an immediate-release opioid indicated only for breakthrough pain in opioid-tolerant cancer patients. Do not use in opioid-naive patients due to risk of fatal respiratory depression. The tablet must not be split, crushed, or chewed; place in buccal cavity. Onset of analgesia occurs within 15 minutes. Due to QT prolongation risk, avoid use with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) and in patients with electrolyte abnormalities. Follow single-tablet administration and wait at least 2 hours before treating another episode. Tear the blister pack before placing; do not store opened blister. |
| Patient Advice | Use only for breakthrough pain if you are already taking around-the-clock opioid medication and are tolerant to it. · Do not use this medicine if you have not taken opioids before; it can cause life-threatening breathing problems. · Place the entire tablet in your cheek pouch above a back molar; do not crush, chew, or swallow it. · Allow tablet to dissolve completely; do not eat or drink until it has fully dissolved (about 14–25 minutes). · If you get more than one breakthrough pain episode per day, contact your doctor; do not increase the dose on your own. · Store in original sealed blister pack; keep out of reach of children and dispose of unused tablets properly. · Avoid alcohol and grapefruit juice while using this medicine. · Do not drive or operate machinery until you know how this medicine affects you. |
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