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. |
| Molecular Weight | 337.46 |
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 | Insufficient human data; animal studies show risk. Avoid use in first trimester unless benefit outweighs risk. |
| 2nd trimester | Limited human data; potential for fetal harm. Use only if clearly needed. |
| 3rd trimester | May cause neonatal withdrawal syndrome. Avoid near term unless necessary. |
Clinical note
Comprehensive clinical and safety monograph for TUZISTRA XR (TUZISTRA XR).
| Placental transfer | Crosses placenta; extent unknown but likely due to molecular weight and lipophilicity. |
| Breastfeeding | Excreted in human milk in low amounts; monitor infant for sedation and poor feeding. Use with caution in breastfeeding women. |
| Lactation Rating |
■ 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 any componentConcurrent use of MAO inhibitorsSevere hepatic impairment
| 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 |
| Food/Dietary |
Loading safety data…
| L3 (Moderately Safe) |
| 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. |
| 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. |
| Take with food to reduce gastrointestinal upset. Avoid high-fat meals as they may delay absorption. Do not consume acidic foods or vitamin C supplements within 1 hour of dosing as they may affect drug absorption. Avoid alcohol. |
| Clinical Pearls | TUZISTRA XR (dextroamphetamine/amphetamine extended-release) is a CNS stimulant indicated for ADHD. Monitor for growth suppression in pediatric patients, and assess for pre-existing cardiovascular conditions. Avoid concurrent use with MAOIs or within 14 days of discontinuation. Administer capsule contents sprinkled on applesauce if swallowing difficulty. Use lowest effective dose and avoid late evening doses to prevent insomnia. |
| Patient Advice | Take exactly as prescribed; do not crush or chew capsules. · Avoid alcohol while taking this medication. · Report any chest pain, shortness of breath, or fainting immediately. · Do not take with or within 14 days of MAOIs. · Possible side effects include decreased appetite, trouble sleeping, and increased heart rate. · Store at room temperature away from moisture and heat. |