Efficacy and tolerability of intranasal fentanyl spray in cancer patients with breakthrough pain.

PURPOSE: The aims of this study were to explore the efficacy of intranasal fentanyl spray* (INFS) 400 µg to evaluate 12-week tolerability of the nasal mucosa and to explore safety data for all dose strengths of INFS in patients with cancer-related breakthrough pain (BTP). METHODS: Patients received a test dose of INFS 50 µg, followed by a titration phase. Those patients with doses titrated to 200 or 400 µg entered a randomized, double-blind, cross-over efficacy phase, in which 8 episodes of BTP were randomly treated with INFS 400 µg (6 episodes) and placebo (2 episodes), followed by a tolerability phase. Patients with doses titrated to 50 or 100 µg entered the tolerability phase directly. Primary outcome was measured by pain intensity difference at 10 minutes, analyzed using ANCOVA, and presented as least square mean difference. Examination of the nasal cavity was conducted at inclusion and after 12 weeks of treatment by an otorhinolaryngologist. FINDINGS: Forty-six patients were included. Thirty-eight patients' doses were titrated to an effective dose of INFS; 50 µg (n = 8), 100 µg (n = 9), 200 µg (n = 9), and 400 µg (n = 12); 15 patients entered the efficacy phase and 31 entered the tolerability phase. In the efficacy phase, 88 and 29 episodes of BTP were treated with INFS 400 µg and placebo, respectively. Pain intensity difference at 10 minutes least square mean for INFS 400 µg was 2.5 (95% CI, 1.42-3.49) (P < 0.001) and least square mean difference between INFS 400 µg and placebo was 1.1 (95% CI, 0.41-1.79) (P = 0.002). Runny nose (10%) and change in color of the mucosa (9%) were the most frequent findings of nasal examination, and nausea and dizziness were the most frequent treatment-related adverse events. One serious adverse event (ie, respiratory depression) was considered related to INFS. IMPLICATIONS: INFS 400 µg is effective and nasal tolerability and overall safety profile is acceptable during 12 weeks of use. ClinicalTrials.gov identifier: NCT01429051.

Faster absorption and higher systemic bioavailability of intranasal fentanyl spray compared to oral transmucosal fentanyl citrate in healthy subjects.

CONTEXT: Intranasal fentanyl spray (INFS) was developed for the treatment of breakthrough pain in cancer patients using an alternative route of administration. OBJECTIVE: The aim of this clinical study was to investigate the pharmacokinetic (PK) profile and bioavailability of INFS in healthy subjects compared to oral transmucosal fentanyl citrate (OTFC). MATERIALS AND METHODS: In a randomized, single-center, open-label, two-way crossover PK study, 24 subjects (12 male, 12 female, mean age 25.2 years) received INFS (single-dose delivery system 200 µg/100 µl) and OTFC (buccal lozenge, 200 µg). Naltrexone was given to prevent potential adverse reactions. Frequent plasma samples were taken up to 96 h and analyzed by LC-MS/MS with a lower limit of quantitation of 25 pg/ml. Primary PK parameter was the area under the fentanyl plasma concentration-time curve (AUC(0-inf)). RESULTS: Compared to OTFC, a much faster absorption rate was observed for INFS which was supported by the much earlier appearance of detectable fentanyl plasma levels and a shorter T(max). At 15 min post-dose, the mean plasma fentanyl levels reached 602 pg/ml for INFS and 29 pg/ml for OTFC. Significantly higher C(max) and AUC values were obtained with INFS compared to OTFC. Although administered for 15 min, consumption of OTFC was incomplete in many incidences (∼70%) upon visual inspection. No safety concerns were identified for fentanyl administration in combination with oral naltrexone. DISCUSSION AND CONCLUSION: One dose of INFS gives significantly higher plasma fentanyl levels and significantly higher bioavailability than OTFC based on dose-normalized AUC.

Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study.

BACKGROUND: Intranasal fentanyl spray (INFS, Instanyl®) was developed to treat cancer patients with Breakthrough Pain (BTP). INFS is delivered via a multi-dose delivery system (MDS) that is available in various dose strengths. The aim of this study was to demonstrate the pharmacokinetic bioequivalence of INFS single dose delivery system (SDS) in relation to the currently marketed MDS device. METHODS: In a randomized, single-center, single-dose, open label, comparative, four-period, two-sequence, replicate cross-over study, 48 healthy subjects (24 male and 24 female, mean age of 28.1 years, mean bodyweight 69.8 kg) received 200 µg/100 µl fentanyl administered via SDS and via MDS in one of two alternating treatment sequences. Naltrexone was given to all subjects to prevent potential fentanyl adverse drug reactions. Blood samples were frequently taken up to 72 hours post INFS administration and analyzed by liquid chromatography with tandem mass spectrometric detection. Primary pharmacokinetic parameters were area under the curve extrapolated to infinity (AUC0-∞) and peak plasma concentration (Cmax). Statistical analyses of the primary pharmacokinetic parameters were performed using a linear mixed effect model applied to the natural log-transformed data. RESULTS: Healthy subjects showed very similar plasma concentration over time profiles for both delivery systems. The mean fentanyl Cmax and AUC0-∞ values for SDS and MDS were 948 pg/ml, 949 pg/ml and 4,439 pg×h/ml, 4,489 pg×h/ml. respectively. Point estimates (and 90% confidence intervals) for AUC and Cmax were 0.97 (0.93 - 1.02) and 1.00 (0.92 - 1.09) and therefore in the bioequivalence range of 0.80 - 1.25. CONCLUSIONS: Results of this study show that SDS and MDS met the pre-defined regulatory criteria for bioequivalence. Safety profiles were consistent between both devices and no safety concerns were identified with INFS administered in combination with oral naltrexone.

A physiologically-based recirculatory meta-model for nasal fentanyl in man.

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available from a study of a nasal delivery system for the opioid analgesic fentanyl, together with data on the kinetics of fentanyl in arterial blood in man, and in the lung and brain of sheep. Our aim was to reconcile these data using a physiologically-based population recirculatory PK-PD model, with emphasis on achieving a meta-model that could simultaneously account for the arterial and venous (arm) concentrations of fentanyl, could relate PD effects (pain scores) to the CNS concentrations of fentanyl, and could account for the effect of body size and age on fentanyl kinetics. Data on the concentration gradients of fentanyl across brain, lung and muscle were used to develop sub-models of fentanyl kinetics in these organs. The sub-models were incorporated into a "whole body" recirculatory model by adding additional sub-models for a venous mixing compartment, the liver and gut, the kidney and the "rest of the body" with blood flows and organ volumes based on values for a Standard Man. Inter-individual variability was achieved by allometric scaling of organ size and blood flows, evidence-based assumptions about the effect of weight and age on cardiac output, and inter-individual variability in the free fraction in plasma and hepatic extraction of fentanyl. Post-operative pain scores were found to be temporally related to the predicted brain concentrations of fentanyl. We conclude that a physiologically-based meta-modelling approach was able to describe clinical PK-PD studies of fentanyl whilst providing a mechanistic interpretation of key aspects of its disposition.

Pharmacokinetics of intranasal fentanyl spray in patients with cancer and breakthrough pain.

OBJECTIVE: This study reports the pharmacokinetics, tolerability, and safety of an intranasalfentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). DESIGN: A randomized, open-label, two-period, crossover trial. PATIENTS: Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. INTERVENTION: Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 microg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. MAIN OUTCOME MEASURE: Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. RESULTS: Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median T(max) values were 15, 12, and 15 minutes for the 50, 100, and 200 microg doses of INFS, respectively. Mean (SD) values for C(max) were 351 (+/- 226), 595 (+/- 400), and 1195 (+/- 700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. CONCLUSION: INFS at doses of 50, 100, and 200 microg showed a short T(max) and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP.

Pharmacokinetics and pharmacodynamics of intranasal versus intravenous fentanyl in patients with pain after oral surgery.

BACKGROUND: Fentanyl, a short-acting synthetic opioid, has a pharmacokinetic profile suited to fast relief of brief episodic pain. OBJECTIVE: To characterize the pharmacokinetic-pharmacodynamic correlation of intranasal and intravenous fentanyl in opioid-naïve patients undergoing third molar extraction. METHODS: A double-blind, double-dummy, crossover design study was conducted, with patients randomized to receive 1 of 4 fentanyl doses (75, 100, 150, or 200 microg) by both the intravenous and intranasal routes. Venous fentanyl concentrations were determined for up to 180 minutes and pain scores were recorded up to 240 minutes postdose. Duration of effect and time to rescue medication were also recorded. RESULTS: The pharmacokinetics of intravenous fentanyl reflected a 2-compartment model with a clearance of approximately 1.5 L/min. There was moderate (<50%) between-subject variability (BSV; %CV [coefficient of variation]) in the systemic kinetics of fentanyl. Bioavailability of intranasal fentanyl was 89%, following first-order absorption, with a lag of approximately 5 minutes and a half-life of approximately 6.5 minutes. Interpatient absorption variability was approximately 30% BSV for all absorption parameters. Intranasal versus intravenous administration led to a delayed mean fentanyl time to maximum concentration (13 vs 6 min) and lower maximum concentration (1.2 vs 2.0 ng/mL). Analgesic effect lagged behind the venous fentanyl concentration, with a half-life of approximately 2.5 minutes as described by a fractional sigmoid maximum drug effect dynamic model. The concentration-analgesia relationship was steep, with a 50% effective concentration of 0.46 ng/mL (Hill coefficient 3.5). Intranasal onset and offset of analgesia were slightly delayed, principally due to the delay and lag in systemic absorption, with slightly lower peak analgesic effect, compared with intravenous fentanyl. Duration of effect was directly related to intranasal fentanyl dose, with pain scores returning to predose values at approximately 120 minutes (75 microg) to approximately 240 minutes (200 microg) after a single dose. CONCLUSIONS: Intranasal fentanyl showed kinetic and dynamic properties that are desirable for the management of acute, episodic (breakthrough) pain.

Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: a randomized, double-blind, double-dummy, two-way, crossover study.

OBJECTIVE: The aim of this study was to compare the pharmacokinetic profile, as well as the efficacy and tolerability, of i.n. and i.v. administration of fentanyl in acute, episodic pain in patients undergoing third-molar extraction. METHODS: In this randomized, double-blind, double-dummy, 2-way, crossover study, patients were randomized to receive 1 of 4 doses (75, 100, 150, or 200 microg) by both the i.n. and i.v. routes in random order, after each of 2 separate molar extractions (interval, >or=1 week). Venous blood samples were obtained for quantification of plasma fentanyl concentrations before and at 1, 3, 5, 7, 9, 12, 15, 25, 40, 60, 90, 120, and 180 minutes after administration. Pain scores (on an 11-point numeric rating scale) were recorded before and at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. Patients indicated the times at which they perceived meaningful pain relief (onset of action) and at which analgesia ended (duration of effect), after which they were able to use rescue medication (time to rescue medication use). RESULTS: A total of 24 patients were enrolled (in all, 47 extractions) (46% male; mean age, 24.1 years; 94% white, 6% Asian). Mean T(max) values were 12.8 and 6.0 minutes (P<0.001), times to onset of analgesia were 7 and 2 minutes (P<0.001), and durations of effect were 56 and 59 minutes after i.n. and i.v. administration (P=NS), respectively. Differences in the onsets and durations of analgesia after i.n. and i.v. administration of single doses were not significantly different, and neither was the difference in overall analgesia, with pain scores returning to near-predose values at statistically similar times after dosing. Duration of effect was directly related to i.n. fentanyl dose, with significantly less use of rescue medication after i.n. than after i.v. administration (P<0.005). The i.n. and i.v. formulations were both well tolerated, with similar numbers of nasally related adverse events recorded for both routes of administration. CONCLUSIONS: Onsets and durations of analgesia were not significantly different between single doses of i.n. and i.v. fentanyl in these adults undergoing third-molar extraction. Both i.n. and i.v. administration were generally well tolerated.