TUZISTRA XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TUZISTRA XR (TUZISTRA XR).
Tuzistra XR is a combination of codeine (an opioid agonist) and promethazine (a phenothiazine derivative with antihistaminic, sedative, and anticholinergic effects). Codeine binds to mu-opioid receptors in the CNS, inhibiting cough reflex. Promethazine acts as a histamine H1 receptor antagonist and may have additional central anticholinergic and sedative effects.
| Metabolism | Codeine is metabolized primarily by CYP2D6 to morphine, and by CYP3A4 to norcodeine; promethazine is metabolized by CYP2B6, CYP2D6, and possibly other enzymes. |
| Excretion | Primarily hepatic metabolism via glucuronidation; approximately 20% of the dose is excreted unchanged in urine, and 80% is eliminated as metabolites in feces via biliary excretion. |
| Half-life | Terminal elimination half-life is 7 hours for the parent drug; clinically, this supports twice-daily dosing for sustained symptom relief. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 0.3 L/kg, indicating distribution primarily into extracellular fluid and limited tissue penetration. |
| Bioavailability | Oral extended-release: approximately 85%. |
| Onset of Action | Oral extended-release: clinical effect observed within 1 hour, with peak plasma concentrations at 6-8 hours post-dose. |
| Duration of Action | Duration of action is approximately 12 hours; clinical effect persists for the dosing interval of 12 hours when taken twice daily. |
Initial: 25 mg orally twice daily; may increase to 50 mg twice daily after 1 week based on tolerability; maximum 50 mg twice daily.
| Dosage form | SUSPENSION, EXTENDED RELEASE |
| Renal impairment | GFR 15-29 mL/min: 25 mg once daily. GFR <15 mL/min or dialysis: 25 mg once daily (limited data); use with caution. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Recommended starting dose is 25 mg once daily; not recommended for Child-Pugh Class C. |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established in patients <18 years. |
| Geriatric use | No specific dose adjustment, but elderly patients may have increased sensitivity; start at 25 mg twice daily and titrate cautiously. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TUZISTRA XR (TUZISTRA XR).
| Breastfeeding | Unknown if excreted in human milk. M/P ratio not determined. Due to potential for serious adverse reactions in nursing infants, discontinue breastfeeding or discontinue drug, considering importance to mother. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Limited human data; animal studies show increased fetal resorptions and skeletal abnormalities at doses >2x MRHD. Second/third trimester: Risk of fetal arrhythmias, growth restriction, and placental hypoperfusion due to maternal hypotension. Avoid in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
WARNING: SERIOUS AND LIFE-THREATENING EVENTS WITH CONCOMITANT USE OF BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ADDICTION, ABUSE, AND MISUSE; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4, 2D6 INTERACTION; RISKS FROM CONCOMITANT USE WITH ALCOHOL OR OTHER CNS DEPRESSANTS.
| Serious Effects |
["Hypersensitivity to codeine, promethazine, or any component","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such use","Gastrointestinal obstruction (e.g., paralytic ileus)","Children less than 6 years of age (due to risk of fatal respiratory depression)","Postoperative management of tonsillectomy/adenoidectomy in children"]
| Precautions | ["Respiratory depression (especially in children)","Addiction, abuse, and misuse","Interaction with CNS depressants (benzodiazepines, alcohol)","Risk of life-threatening respiratory depression in children with ultra-rapid CYP2D6 metabolism","Neonatal opioid withdrawal syndrome with prolonged use during pregnancy","Serotonin syndrome with concomitant serotonergic drugs","Severe hypotension","Adrenal insufficiency","Risk of seizures in patients with epilepsy","Anticholinergic effects (promethazine): dry mouth, urinary retention, blurred vision","Prolonged QT interval risk with promethazine"] |
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| Fetal Monitoring |
| Monitor maternal blood pressure and heart rate frequently. Fetal monitoring for heart rate decelerations or arrhythmias. Serial ultrasound for fetal growth restriction. Assess for signs of placental insufficiency. |
| Fertility Effects | No human fertility studies. In animal studies, no impairment of fertility was observed at doses up to 10 mg/kg/day in rats. Human impact unknown. |