A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Combunox Pharmacology, Pharmacokinetics, Studies, Metabolism - Oxycodone HCL and Ibuprofen
Combunox Pharmacology, Pharmacokinetics, Studies, Metabolism - Oxycodone HCL and Ibuprofen
CLINICAL PHARMACOLOGY
Oxycodone HCl component
Oxycodone HCl is a semisynthetic opioid analgesic with multiple
actions which involve the central nervous system and smooth muscle. The mechanism
of action of oxycodone is not known but is thought to be related to its binding
to opiate receptors in the central nervous system. In addition to analgesia,
opioids may produce sedation and respiratory depression.
Ibuprofen component
Ibuprofen is a nonsteroidal anti-inflammatory agent that possesses
analgesic and antipyretic activities. Its mode of action, similar to other NSAIDs,
is not completely understood, but is thought to be related to its 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
Oxycodone is rapidly absorbed after single dose administration
of Combunox. Maximum concentrations (Cmax) of oxycodone, ranging
from 9.8 ng/mL to 11.7 ng/mL, are obtained within 1.3 hr to 2.1 hr after administration
of Combunox. Repeated administration of Combunox every 6 hours results in approximately
50-65% increase in Cmax. In the presence of food, the bioavailability
of oxycodone is slightly (25%) increased.
Ibuprofen is rapidly absorbed after oral administration of
Combunox. Cmax values range from 18.5 mcg/mL to 34.3 mcg/mL and are
reached 1.6 hr to 3.1 hr after oral administration of Combunox. Repeated administration
of Combunox every 6 hours does not result in any accumulation of ibuprofen.
The bioavailability of ibuprofen is not altered in the presence of food.
Distribution
Oxycodone binding to protein in serum is approximately 45%.
Ibuprofen is extensively bound to plasma proteins (99%).
Metabolism
Oxycodone is metabolized in the liver by means of N-demethylation
and O-demethylation, 6-ketoreduction and glucuronidation. The major circulating
metabolite is noroxycodone, which possesses weak analgesic activity.
Oxymorphone, the end product of O-demethylation, has analgesic
activity but is present in the plasma at low concentrations. Metabolism of oxycodone
to oxymorphone occurs via CYP2D6.
Ibuprofen is present 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'-(2-hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2-carboxypropyl)
phenyl propionic acid, both of which circulate in the plasma at low levels relative
to the parent.
Elimination
Oxycodone is eliminated from the systemic circulation with
half life (T1/2) values ranging
from 3.1 hr to 3.7 hr after single dose administration of Combunox.
Urinary excretion of unchanged oxycodone amounts to approximately 4% of the
administered oxycodone dose.
Ibuprofen is eliminated from the systemic circulation with
half life (T1/2) values ranging from 1.8 hr to 2.6 hr after single
dose administration of Combunox. Urinary excretion of unchanged ibuprofen is
minimal (less than 0.2% of administered ibuprofen dose).
Special Populations
Gender
There are no gender effects on the pharmacokinetics of oxycodone
or ibuprofen after administration of Combunox.
Age
The effects of age on the pharmacokinetics of oxycodone and
ibuprofen after administration of Combunox have not been evaluated.
When either drug was administered alone, the pharmacokinetics
of oxycodone and ibuprofen were similar in elderly subjects, compared to young
healthy subjects.
Pediatrics
The pharmacokinetics of oxycodone and ibuprofen after administration
of Combunox have not been evaluated in a pediatric population.
Renal Impairment
The effects of renal impairment on the pharmacokinetics of
oxycodone and ibuprofen after administration of Combunox have not been evaluated.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of
oxycodone and ibuprofen after administration of Combunox have not been evaluated.
(See PRECAUTIONS; Hepatic Effects)
CLINICAL STUDIES
Combunox was investigated in three clinical studies. Two studies
involving a total of 949 patients following dental surgery (removal of ipsilateral
molars) and a third study of 456 patients following abdominal/pelvic surgery
were conducted. In the three studies patients were administered a single dose
of the Combunox, ibuprofen alone, oxycodone HCl alone or placebo for acute,
moderate to severe pain.
In these single dose studies, Combunox produced greater efficacy
than placebo and each of Combunox’s individual components as measured by the
magnitude of pain relief and the reduction in pain intensity through six hours.
No multiple dose efficacy studies have been performed with Combunox.
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