ZYDONE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZYDONE (ZYDONE).
Hydrocodone is a mu-opioid receptor agonist; acetaminophen produces analgesia via central COX inhibition and activation of descending serotonergic pathways.
| Metabolism | Hydrocodone: CYP3A4 and CYP2D6; acetaminophen: primarily glucuronidation via UGT1A1, UGT1A6, and UGT1A9, with minor oxidation via CYP2E1 and CYP1A2. |
| Excretion | Approximately 60% of hydrocodone and its metabolites are excreted renally as glucuronide conjugates; ~10% as norhydrocodone, hydromorphone, and other metabolites. Fecal excretion accounts for less than 5%. Total renal elimination: ~65-70%. |
| Half-life | Terminal elimination half-life of hydrocodone is 3.8-4.5 hours in healthy adults; prolonged in elderly or hepatic impairment (up to 6-8 hours). Clinical context: dosing interval typically every 4-6 hours, adjusted for renal/hepatic insufficiency. |
| Protein binding | Hydrocodone is approximately 20-30% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Hydrocodone has a volume of distribution of approximately 3.5-5.5 L/kg, indicating extensive tissue distribution and sequestration in peripheral compartments. |
| Bioavailability | Oral bioavailability of hydrocodone is 50-70% due to first-pass metabolism. |
| Onset of Action | Oral: 10-20 minutes after administration, with peak effect at 30-60 minutes. |
| Duration of Action | Analgesic duration: 4-6 hours after oral administration. Clinical note: duration may be shorter with single-dose and longer with repeated dosing due to accumulation. |
| Molecular Weight | 299.4 g/mol (hydrocodone bitartrate); 151.2 g/mol (acetaminophen). Combined preparation: individual components. |
Oral: 1 to 2 tablets every 4 to 6 hours as needed for pain. Each tablet contains hydrocodone bitartrate 5 mg and acetaminophen 500 mg (Zydone 5/500). Maximum acetaminophen dose: 4000 mg/day (8 tablets).
| Dosage form | TABLET |
| Renal impairment | For CrCl 30-50 mL/min: reduce dose to 50% of normal and extend dosing interval to every 6 hours. For CrCl <30 mL/min: avoid use due to risk of acetaminophen accumulation and hydrocodone toxicity. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50% and monitor; Class C: avoid use due to risk of hepatic encephalopathy and toxicity. |
| Pediatric use | Not recommended for children <18 years due to risk of respiratory depression and lack of safety data. |
| Geriatric use | Initiate at 50% of adult dose (e.g., 0.5 tablet every 6 hours) and titrate cautiously due to increased sensitivity to opioids and risk of falls, cognitive impairment, and constipation. |
| 1st trimester | Limited human data; animal studies have shown teratogenic effects at high doses. Use only if potential benefit justifies risk. Consider alternative agents. |
| 2nd trimester | May cause fetal respiratory depression and withdrawal if used chronically near term. Use with caution; monitor fetal movements. |
| 3rd trimester | Avoid use in late pregnancy (especially third trimester) due to risk of neonatal opioid withdrawal syndrome and respiratory depression. |
Clinical note
Comprehensive clinical and safety monograph for ZYDONE (ZYDONE).
| Placental transfer | Both hydrocodone and acetaminophen cross the placenta. Hydrocodone is transferred to the fetus with a cord-to-maternal plasma concentration ratio of approximately 0.8–1.0. |
| Breastfeeding | Hydrocodone (component of Zydone) is excreted into breast milk in low amounts. In mothers with normal CYP2D6 activity, it is generally considered compatible with breastfeeding; however, caution is advised in mothers who are ultrarapid metabolizers of CYP2D6, as this may lead to higher levels of the active metabolite hydromorphone and potential infant toxicity. Monitor infant for signs of sedation and respiratory depression. |
■ FDA Black Box Warning
Risk of medication errors (confusion between immediate-release and extended-release products); addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; interactions with alcohol or central nervous system depressants; hepatotoxicity from acetaminophen overdose.
| Serious Effects |
Hypersensitivity to hydrocodone, acetaminophen, or any componentSignificant respiratory depressionAcute or severe bronchial asthmaParalytic ileusKnown or suspected gastrointestinal obstruction
| Precautions | Respiratory depression, drug dependence, abuse potential, CNS depression, hepatotoxicity (acetaminophen), adrenal insufficiency, hypotension, seizures, severe hypotension, gastrointestinal obstruction, and anaphylaxis. |
| Food/Dietary | Avoid alcohol and grapefruit juice (may alter hydrocodone metabolism). No significant food restrictions otherwise. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show increased risk of neural tube defects and skeletal anomalies at maternally toxic doses. Second and third trimesters: Associated with neonatal respiratory depression, withdrawal syndrome, and reduced fetal growth. Risk of preterm birth and low birth weight. Avoid use unless maternal benefit outweighs fetal risk. |
| Fetal Monitoring | Maternal: Heart rate, blood pressure, oxygen saturation, pain scores, signs of respiratory depression. Fetal: Nonstress test or biophysical profile in third trimester if chronic use. Neonatal: Monitor for withdrawal symptoms (e.g., irritability, poor feeding, tremors) and respiratory status for 24-48 hours postpartum. |
| Fertility Effects | May impair female fertility in animal studies (prolonged estrous cycles). No human data on male fertility; possible oligospermia with chronic opioid use. Reversible upon discontinuation. |
| Clinical Pearls | ZYDONE is a combination of hydrocodone and acetaminophen. Monitor for hepatotoxicity due to acetaminophen; max daily dose 4 g (preferably 3 g in at-risk patients). Hydrocodone is a prodrug metabolized by CYP2D6; poor metabolizers may have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Use with caution in patients with respiratory compromise, COPD, or sleep apnea. Avoid alcohol and other CNS depressants. Prescribe lowest effective dose for shortest duration. In pregnancy, prolonged use may cause neonatal opioid withdrawal syndrome. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Do not exceed 4,000 mg of acetaminophen per day from all sources; check other medications for acetaminophen content. · Avoid alcohol while taking this medication; alcohol increases risk of liver damage. · This medication can cause drowsiness or dizziness; avoid driving or operating machinery until you know how it affects you. · Do not stop abruptly; withdrawal symptoms may occur if taken for more than a few days. · Store securely out of reach of children and others; accidental overdose can be fatal. · Report any signs of liver problems: yellowing of skin/eyes, dark urine, abdominal pain. |