TREZIX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TREZIX (TREZIX).
Capsaicin is a TRPV1 receptor agonist that initially causes pain and neuropeptide release, followed by desensitization and depletion of substance P from sensory nerve terminals, reducing pain transmission. Hydrocodone is a mu-opioid receptor agonist, modulating pain perception. Acetaminophen inhibits cyclooxygenase (COX) enzymes, primarily in the central nervous system, reducing prostaglandin synthesis and pain signaling.
| Metabolism | Hydrocodone: Hepatic metabolism via CYP2D6 and CYP3A4 to hydromorphone and norhydrocodone, respectively. Acetaminophen: Conjugation primarily via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation (SULT1A1), with minor CYP2E1 oxidation to NAPQI. |
| Excretion | Renal excretion of metabolites (primarily as glucuronide conjugates and unchanged drug) accounts for approximately 55-65% of the dose; biliary/fecal elimination accounts for approximately 25-35%. |
| Half-life | Terminal elimination half-life is approximately 2.5-3.5 hours for the parent compound; clinically, this necessitates dosing every 4-6 hours for sustained effect during wakefulness, but accumulation is minimal with normal hepatic and renal function. |
| Protein binding | Approximately 35-40% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 3-4 L/kg, indicating extensive tissue distribution with penetration into the central nervous system. |
| Bioavailability | Oral bioavailability is approximately 50-70% due to first-pass hepatic metabolism. |
| Onset of Action | Oral administration: onset of clinical effect occurs within 20-30 minutes. |
| Duration of Action | Duration of action is approximately 4-6 hours after oral administration; clinical notes: the antitussive effect typically lasts for the dosing interval, but tolerance may develop with prolonged use. |
TREZIX (acetaminophen 320 mg, dichloralphenazone 100 mg, isometheptene mucate 65 mg) capsules: 2 capsules orally at onset of headache, then 1 capsule every hour until relief (maximum 5 capsules in 12 hours, 10 capsules in 24 hours). For migraine: 2 capsules orally at onset, then 1 capsule every hour as needed (maximum 5 capsules per attack).
| Dosage form | CAPSULE |
| Renal impairment | No specific GFR-based dose adjustments available; contraindicated in severe renal impairment (CrCl <30 mL/min) due to acetaminophen and dichloralphenazone accumulation. Use with caution in moderate impairment (CrCl 30-60 mL/min); consider extending dosing interval to every 6-8 hours. |
| Liver impairment | Contraindicated in Child-Pugh class C (severe hepatic impairment). In Child-Pugh class A or B: reduce dose by 50% and monitor liver function; maximum acetaminophen daily dose should not exceed 2000 mg. Avoid in active liver disease. |
| Pediatric use | Not recommended for children under 12 years due to lack of safety data. For adolescents 12-17 years: 1-2 capsules orally at onset, then 1 capsule every hour as needed (maximum 3 capsules in 12 hours). Weight-based dosing not established. |
| Geriatric use | Initiate with lower dose (1 capsule at onset) and monitor closely due to increased sensitivity to anticholinergic effects of dichloralphenazone. Maximum daily acetaminophen dose not to exceed 3000 mg. May require longer dosing intervals (every 6-8 hours). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TREZIX (TREZIX).
| Breastfeeding | No specific studies for TREZIX. Acetaminophen is compatible with breastfeeding (M/P ratio ~1.0). Dichloralphenazone (metabolized to trichloroethanol) and isometheptene: data lacking. Barbiturate metabolites may cause infant sedation, poor feeding, and withdrawal risk. Manufacturer advises caution; use alternative if possible. |
| Teratogenic Risk | TREZIX (acetaminophen, dichloralphenazone, isometheptene) is contraindicated in pregnancy. First trimester: risk of neural tube defects and other malformations due to acetaminophen? limited data but dichloralphenazone is a barbiturate derivative with known teratogenicity (cleft palate, cardiac defects). Second and third trimesters: barbiturates may cause neonatal dependence, withdrawal, and bleeding disorders (vitamin K deficiency). Late third trimester: maternal use of barbiturates may lead to neonatal respiratory depression and withdrawal. Avoid in all trimesters. |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; HEPATOTOXICITY (due to acetaminophen); RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
| Serious Effects |
Hypersensitivity to any ingredient; significant respiratory depression; acute or severe bronchial asthma in unmonitored settings; known or suspected gastrointestinal obstruction; concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days; severe hepatic impairment (due to acetaminophen).
| Precautions | Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risks with CYP3A4 inhibitors or discontinuation; hepatotoxicity from acetaminophen overdose; hypersensitivity reactions; severe hypotension; gastrointestinal obstruction; seizures; serotonin syndrome with concomitant serotonergic drugs; impaired mental/physical abilities; adrenal insufficiency; androgen deficiency. |
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| Fetal Monitoring | Monitor maternal blood pressure (isometheptene may cause hypertension), liver function (acetaminophen hepatotoxicity with overdose), and neurological status (barbiturate sedation). Fetal monitoring: consider nonstress test and biophysical profile in third trimester if used inadvertently. Neonatal monitoring: observe for withdrawal signs (irritability, tremors, seizures) in neonates exposed near term. |
| Fertility Effects | No formal studies. Barbiturates may impair fertility via hypothalamic-pituitary axis disruption (anovulation, menstrual irregularities). Isometheptene sympathomimetic effects may affect ovarian blood flow theoretically. Acetaminophen at high doses may affect female fertility (prolonged time to pregnancy); effects on male fertility unknown. |