JURNISTA Prolonged-release tablet Ref.[50341] Active ingredients: Hydromorphone

Absorption

Following a single oral dose of JURNISTA prolonged-release tablets, plasma concentrations gradually increase over 6 to 8 hours and thereafter concentrations are sustained for approximately 18 to 24 hours post-dose; the mean t_max values were approximately 13 to 16 hours. This demonstrates that, as intended, hydromorphone is released in a consistent manner from the dosage form, with drug absorption continuing throughout the intestinal tract for approximately 24 hours, consistent with once-daily dosing. The mean absolute bioavailability of hydromorphone after a single dose of 8, 16 or 32 mg of JURNISTA ranged from 22% to 26%. The concomitant administration of JURNISTA with a high fat meal has no effect on the absorption of hydromorphone.

Steady state plasma concentrations are approximately twice those observed following the first dose, and steady state is reached by the fourth dose of JURNISTA. No time dependent change in pharmacokinetics was seen with multiple dosing. At steady state, JURNISTA given once daily maintained hydromorphone plasma concentrations within the same concentration range as an immediate-release tablet given 4-times daily at the same total daily dose and diminishes the periodic fluctuations in plasma levels seen with the immediate-release tablet. The degree of fluctuation in plasma concentration at steady state during a 24-hour period (calculated as (C_max(ss) – C_min(ss))/C_avg(ss) x 100%) was lower with JURNISTA (83%) as compared to the overall fluctuations of the immediate-release tablet (147%). At steady state, hydromorphone AUC for JURNISTA is equivalent to that observed for the immediate-release tablet.

Distribution

Plasma protein binding is low (<30%).

Biotransformation

Glucuronidation is the main metabolic pathway and the principal metabolite is hydromorphone 3-glucuronide, which follows a similar time course to hydromorphone in plasma. Unlike morphine, no 6-glucuronide is produced.

Linearity

Linear pharmacokinetics have been demonstrated for the controlled release tablet over the dose range 4 to 64 mg, with dose proportional increase in plasma concentrations (C_max) and overall exposure (AUC).

Elderly

The effect of age on the single-dose pharmacokinetics of hydromorphone immediate-release resulted in a 14% decrease in C_max and a modest increase (11%) in AUC in the elderly compared to the young. No difference in Tmax was observed. Greater sensitivity of older individuals cannot be excluded. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.

Gender

Hydromorphone plasma concentrations and pharmacokinetic parameters following administration of JURNISTA are comparable in male and female subjects.

Renal impairment

Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites hydromorphone 3-glucuronide and 3-sulfate following administration of a single oral dose of the immediate-release tablet. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and fourfold increases in hydromorphone bioavailability in moderate and severe impairment, respectively. There were also substantial changes in hydromorphone 3-glucuronide elimination kinetics for the severe impairment group, although haemodialysis was effective at reducing plasma levels of both hydromorphone and metabolites. See section 4.2 for recommendations on dosage.

Hepatic impairment

In studies that used single oral dosing with conventional (immediate-release) tablets, hepatic impairment reduces the first-pass metabolism of hydromorphone such that four-fold higher plasma levels of hydromorphone are seen in subjects with moderate hepatic dysfunction. See section 4.2 for recommendations on dosage.

Alcohol

In a study comparing hydromorphone absorption from JURNISTA when taken with 240 ml of 4%, 20% and 40% alcohol, C_max increased on average by 17, 31, and 28% respectively in the fasting state and was less affected in the fed state with increases of 14, 14, and 10%, respectively. Median T_max (fed and fasted) taken with 4, 20 and 40% alcohol was 12-16 h and with 0% alcohol was 16 h. No effect was seen on AUC values both in the fed and fasted state. Due to the OROS technology in JURNISTA, the prolonged-release properties of JURNISTA are maintained in the presence of alcohol. For the pharmacodynamic interactions, see section 4.4.

Non-clinical data from oral administration of hydromorphone reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and fertility. In the rat, a slight but statistically significant reduction in implantations was observed at 6.25 mg/kg/day, a dose level that produced maternal toxicity during the mating period. Plasma exposure (AUC) to hydromorphone at this dose level was 135 ng.hr/mL, providing a safety factor of about 1.5 over the human exposure (AUC) based on the median daily dose. Neonatal viability and survival were reduced in rats pre-weaning, at the maternal oral daily dose of 6.25 mg/kg. The latter appears to be a class effect of an opioid analgesic.

Long-term studies of hydromorphone showed no evidence of any carcinogenic effects after daily oral dosing for 2 years in mice and rats. The steady state plasma exposure (AUC, ng.hr/mL) to hydromorphone in mice was approximately 0.46-times and in rats was greater than 3-times the human exposure following a single 64 mg dose of JURNISTA.