Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Napp Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge CB4 0GW
Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids
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 binds to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid receptors.
Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is <3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function disorders that are typical for opioid treatment.
For effects of opioids upon the endocrine system, see section 4.4.
Preclinical studies show differing effects of natural opioids on components of the immune system. The clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic opioid, has similar effects on the immune system to natural opioids.
In a 12 weeks parallel group double-blinded study in 322 patients with opioid-induced constipation, patients who were treated with oxycodone hydrochloride-naloxone hydrochloride had on average one extra complete spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was significantly lower in the oxycodone-naloxone group compared to the oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride-naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the same dose range.
In a 12-week double-blind efficacy study, 150 patients with severe to very severe idiopathic restless legs syndrome at randomisation were treated with oxycodone hydrochloride/naloxone hydrochloride. Severe syndrome is defined as IRLS score between 21 and 30, and very severe as score between 31 and 40. Patients showed a clinically relevant and a statistically significant improvement in mean IRLS score compared to placebo during the entire treatment period with a decrease in the mean IRLS score of 5.9 points compared to placebo at week 12 (assuming an effect similar to placebo completers for patients who discontinued the study representing a very conservative approach). The onset of efficacy was demonstrated from as early as week 1 of treatment. Similar results were shown for the RLS symptom severity improvement (as measured by the RLS-6-Rating scale), in quality of life as measured by a QoL-RLS questionnaire, in sleep quality (measured by MOS sleep scale), and for the proportion of IRLS score remitters. No subject had a confirmed case of augmentation during the study
Oxycodone has a high 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 and oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant.
Oxycodone and its metabolites are excreted in both urine and faeces.
Following oral administration, naloxone has a very low 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, 6β-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.
Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (Cmax) of oxycodone were increased by an average of 16% and 30% respectively compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore Targinact prolonged-release tablets may be taken with or without food (see section 4.2).
In vitro drug metabolism studies have indicated that the occurrence of clinically relevant interactions involving Targinact is unlikely.
For AUC 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 AUC 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 AUC 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 naloxone3-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 characterize the naloxone plasma profiles for the healthy subjects.
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For Cmax of naloxone-3-glucuronide, on average there was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For t1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects.
To avoid damage to the prolonged-release properties of the tablets, Targinact must not be broken, crushed or chewed, as this leads to a rapid release of the active substances. In addition, naloxone has a slower elimination rate when administered intranasally. Both properties mean that abuse of Targinact will not have the effect intended. In oxycodonedependent rats, the intravenous administration of oxycodone hydrochloride / naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms.
There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone.
Studies with the single components showed that oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual fetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. The standard oral reproduction toxicity studies with naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/fetotoxic, and does not affect perinatal/postnatal development. At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum period at dosages that produced significant toxicity in maternal rats (e.g., body weight loss, convulsions). However, in surviving pups, no effects on development or behaviour were observed.
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 tumours in male and female rats at doses up to 6mg/kg/day. The doses were limited by opioidrelated pharmacological effects of oxycodone.
For naloxone, a 24-months 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 is not carcinogenic under these conditions.
Oxycodone and naloxone as single entities show a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of Targinact to humans at therapeutic concentrations may be ruled out with adequate certainty.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
