CLINICAL PHARMACOLOGY
Hydrocodone Component
Hydrocodone is a semisynthetic opioid analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opioids is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, opioids may produce drowsiness, changes in mood, and mental clouding.
Ibuprofen Component
Ibuprofen is a non-steroidal anti-inflammatory agent that possesses analgesic and antipyretic activities. Its mode action, like that of other NSAIDs, is not completely understood, but may be related to inhibition of cyclooxygenase activity and prostaglandin synthesis. Ibuprofen is a peripherally acting analgesic. Ibuprofen does not have any known effects on opiate receptors.
Pharmacokinetics
Absorption
After oral dosing with the VICOPROFEN tablet, a peak hydrocodone plasma level of 27 ng/mL is achieved at 1.7 hours, and a peak ibuprofen plasma level of 30 mcg/mL is achieved at 1.8 hours. The effect of food on the absorption of either component from the VICOPROFEN tablet has not been established.
Distribution
Ibuprofen is highly protein-bound (99%) like most other non-steroidal anti-inflammatory agents. Although the extent of protein binding of hydrocodone in human plasma has not been definitely determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.
Metabolism
Hydrocodone exhibits a complex pattern of metabolism, including O -demethylation, N -demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. Hydromorphone, a potent opioid, is formed from the O -demethylation of hydrocodone and contributes to the total analgesic effect of hydrocodone. The O - and N -demethylation processes are mediated by separate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively.
Ibuprofen is present in this product as a racemate, and following absorption it undergoes interconversion in the plasma from the R-isomer to the S-isomer. Both the R- and S- isomers are metabolized to two primary metabolites: (+)-2-4'-(2hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2carboxypropyl) phenyl propionic acid, both of which circulate in the plasma at low levels relative to the parent.
Elimination
Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours. Ibuprofen is excreted in the urine, 50% to 60% as metabolites and approximately 15% as unchanged drug and conjugate. The plasma half-life is 2.2 hours.
Special Populations
No significant pharmacokinetic differences based on age or gender have been demonstrated. The pharmacokinetics of hydrocodone and ibuprofen from VICOPROFEN has not been evaluated in children.
Renal Impairment
The effect of renal insufficiency on the pharmacokinetics of the VICOPROFEN dosage form has not been determined.
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