Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Mundipharma (Pty) Ltd, Block D, Grosvenor Square, Park Lane, Century City, 7441, Cape Town, South Africa
A 2.9 Other Analgesics
ATC code: N02AA55
Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and affects pain relief by binding to the endogenous opioid receptors in the CNS. Naloxone is a pure antagonist acting on all types of opioid receptors.
The absolute bioavailability of naloxone upon oral administration is <3%. Naloxone antagonises the opioid receptor mediated oxycodone effect.
Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical symptoms may occur because of these hormone changes.
Oxycodone has an absolute bioavailability of up to 87% following oral administration.
Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein. Oxycodone crosses the placenta and may be detected in breast milk.
Oxycodone is metabolised in the gut and the liver to noroxycodone, oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. The analgesic effects of these metabolites are thought to be clinically insignificant.
Oxycodone and its metabolites are excreted in both urine and faeces.
Following oral administration, naloxone has a systemic availability of <3%.
Naloxone passes into the placenta. It is not known, whether naloxone also passes into breast milk.
After parenteral administration, the plasma half-life is approximately one hour. The duration of action depends upon the dose and route of administration, intramuscular injection producing a more prolonged effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal metabolites are naloxone glucuronide, 6-Naloxol and its glucuronide.
The pharmacokinetic characteristics of oxycodone from TarginAct is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets. All dosage strengths of TarginAct are interchangeable.
After the oral administration of TarginAct in maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since its plasma concentration is high enough to measure.
The peak plasma concentration (Cmax) and bioavailability of oxycodone after ingestion of TarginAct following a high-fat breakfast were increased by an average 16% and 30% respectively compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore TarginAct may be taken with or without food (see section 4.2).
For AUCτ of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly compared with younger volunteers. For Cmax of oxycodone, on average there was an increase to 114% (90% C.I.: 102, 127). For Cmin of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152).
For AUCτ of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared with younger volunteers. For Cmax of naloxone, on average there was an increase to 173% (90% C.I.: 107, 280). For Cmin of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708).
For AUCτ of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for elderly compared with younger volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112, 144). For Cmin of naloxone-3-glucuronide, on average there was an increase to 125% (90% C.I.: 105, 148).
For AUCINF of oxycodone, on average there was an increase to 143% (90% C.I.: 111, 184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
For t1/2Z of oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
For AUCt of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values.
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone-3-glucuronide, on average there was an increase to 141% (90% C.I.: 100, 197), 118% (90% C.I.: 84, 166) and a decrease to 98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.: 72, 161), a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
For AUCINF of oxycodone, on average there was an increase to 153% (90% C.I.: 130, 182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to 110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers.
For AUCt of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an increase to 1076% (90% C.l.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values. The ratios may have been influenced by the inability to fully characterise the naloxone plasma profiles for the healthy subjects.
There are no preclinical data pertaining to the genotoxicity/ carcinogenicity/ reproductive toxicity of the combination of oxycodone and naloxone at the 2:1 ratio. The data presented here are for studies with the single compounds.
Oxycodone and naloxone were each tested as single entities in in vitro and in vivo genotoxicity studies. The results from in vitro clastogenicity assays were equivocal, but neither oxycodone nor naloxone were mutagenic in the in vitro bacterial mutagenicity assay. However, when evaluated in vivo, oxycodone and naloxone were not genotoxic in the mouse bone marrow micronucleus test even at doses that caused significant adverse effects. The weight of evidence indicates that the combination of oxycodone and naloxone poses minimal if any risk for human genotoxicity at systemic concentrations that are achieved therapeutically.
Long-term carcinogenicity studies with oxycodone/naloxone in combination have not been performed.
Carcinogenicity was evaluated in a 2-year oral gavage study conducted in Sprague-Dawley rats. Oxycodone did not increase the incidence of tumors in male and female rats at doses up to 6 mg/kg/day. The doses were limited by opioid-related pharmacological effects of oxycodone.
For naloxone, a 24-month oral carcinogenicity study was performed in rats with doses up to 100 mg/kg/day and a 6 month carcinogenicity study was performed in TgrasH2 mice at doses up to 200 mg/kg/day. The results of the two studies indicate that naloxone was not carcinogenic under these conditions.
Oxycodone and naloxone were not teratogenic, even at maternally toxic doses in rats and rabbits. Oxycodone and naloxone did not affect fertility, reproductive performance or adversely affect long-term development of pups (F1 generation) born to rats treated with oxycodone during late pregnancy and lactation, with the exception of decreased body weights noted at doses associated with maternal toxicity. Moreover, neither oxycodone nor naloxone exhibited any developmental effects on pups born to the F1 generation females.
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