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. |
| Molecular Weight | Acetaminophen: 151.16 Da; Dichloralphenazone: 334.11 Da; Isometheptene: 141.23 Da |
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 | TREZIX (acetaminophen, dichloralphenazone, isometheptene) contains dichloralphenazone, a chloral hydrate derivative. Data for dichloralphenazone in pregnancy are limited. Acetaminophen is generally considered low risk. Isometheptene is a sympathomimetic amine. Teratogenic risk cannot be excluded; use only if clearly needed. |
| 2nd trimester | Similar to t1. Avoid chronic use due to potential risks. Acetaminophen is safe at therapeutic doses. Dichloralphenazone may cause neonatal withdrawal if used near term. |
| 3rd trimester | Near term, dichloralphenazone may cause neonatal sedation, withdrawal, or flaccidity. Isometheptene can cause maternal tachycardia and uterine vasoconstriction. Acetaminophen is safe in standard doses. Caution. |
Clinical note
Comprehensive clinical and safety monograph for TREZIX (TREZIX).
| Placental transfer | Acetaminophen crosses the placenta freely. Dichloralphenazone (chloral hydrate) crosses placenta and accumulates in fetal tissues. Isometheptene likely crosses; evidence limited. |
| Breastfeeding |
■ 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 componentSevere hypertensionCoronary artery diseasePeripheral vascular diseaseGlaucomaMonoamine oxidase inhibitor (MAOI) use within 14 days
| 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. |
| Food/Dietary | Avoid alcohol. Limit caffeine from other sources (coffee, tea, soda) to prevent excessive stimulation. High-fat meals may delay absorption but do not significantly alter overall effect. |
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| Acetaminophen is excreted into breast milk in small amounts and is considered compatible. Dichloralphenazone (chloral hydrate metabolite) passes into milk and may cause sedation in the infant. Isometheptene excretion unknown but potential for sympathomimetic effects. Use lowest effective dose for shortest duration. |
| Lactation Rating | L3 - Moderately Safe |
| 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. |
| 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. |
| Clinical Pearls | TREZIX (acetaminophen, caffeine, and dihydrocodeine) is a fixed-dose combination analgesic with abuse potential; monitor for opioid-induced constipation and respiratory depression. Avoid exceeding 4 grams/day of acetaminophen due to hepatotoxicity risk. Caffeine may potentiate analgesic effects but can cause insomnia and anxiety. Discontinue prior to surgery to avoid withdrawal and respiratory complications. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without doctor approval. · Do not combine with other acetaminophen-containing products to avoid liver damage. · Avoid alcohol while taking this medication. · Do not drive or operate heavy machinery until you know how TREZIX affects you. · Report severe constipation, difficulty breathing, or signs of allergic reaction immediately. · Do not stop suddenly; taper under medical supervision to prevent withdrawal. |