PHARMACOKINETICS AND METABOLISM:

The analgesic activity of DILAUDID (hydromorphone hydrochloride) is due to the parent drug, hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract after oral administration and undergoes extensive first-pass metabolism. Exposure of hydromorphone (C_max and AUC_0-24) is dose-proportional at a dose range of 2 and 8 mg. In vivo bioavailability following single-dose administration of the 8 mg tablet is approximately 24% (coefficient of variation 21%). Bioequivalence between the DILAUDID 8 mg TABLET and an equivalent dose of DILAUDID ORAL LIQUID has been demonstrated.

Absorption: After oral administration of DILAUDID 8 mg liquid or tablets, peak plasma hydromorphone concentrations are generally attained within ½ to 1-hour.

Food effects: In a study conducted with a single 8 mg dose of hydromorphone (2 mg DILAUDID® IR tablets), food lowered C_max by 25%, prolonged T_max by 0.8 hour, and increased AUC by 35%. The effects may not be clinically relevant.

Distribution: At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume distribution [mean (%cv)] is 302.9 (32%) liters.

Metabolism: Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Elimination: Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.

Hepatic Impairment: After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR Tablets), mean exposure to hydromorphone (C_max and AUC∞ is increased 4-fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at a lower dose and closely monitored during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in C_max and AUC of hydromorphone in this group is expected. As such, starting dose should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION.

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