Neha Parikh

Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study

Abstract Background and objectives: A number of transmucosal fentanyl formulations have been developed for the management of breakthrough cancer pain (BTCP). Sublingual delivery of fentanyl, formulated as fentanyl sublingual spray, offers the potential for more rapid and greater absorption of fentanyl and associated onset of analgesic effect compared with other formulations. The objective of this study was to assess the efficacy and safety of fentanyl sublingual spray for the treatment of BTCP. Research design and methods: This was a randomized, double-blind, placebo-controlled phase III trial conducted in opioid-tolerant patients with BTCP. An open-label titration period was followed by a double-blind treatment period during which patients received fentanyl sublingual spray (100–1600 mcg) or placebo. Clinical trial registration: Trial registration: ClinicalTrials.gov identifier: NCT00538850. Main outcome measures: The primary efficacy measure was summed pain intensity difference at 30 minutes (SPID30). Secondary efficacy measures included total pain relief at 30 minutes (TOTPAR30) and patient global evaluation of study medication at 30 minutes. Efficacy measures were also assessed at various time points from 5–60 minutes postdose. Adverse events were monitored throughout the study. Results: A total of 130 patients were treated during the titration period, of whom 98 (75.4%) entered the double-blind period. Relative to placebo, fentanyl sublingual spray significantly improved mean SPID scores from 5 minutes (p = 0.0219) through 60 minutes (p < 0.0001), including the primary endpoint at 30 minutes (p < 0.0001). Fentanyl sublingual spray produced significantly greater pain relief (expressed in terms of TOTPAR) from 5 through 60 minutes (p < 0.0001), and significantly greater global evaluation of treatment effectiveness (p < 0.0001), compared with placebo. During double-blind treatment, the most frequently reported adverse events were nausea (7.1%), hyperhidrosis (5.1%), and peripheral edema (5.1%). Serious adverse events occurred in seven patients (5.4%) during titration and six (6.1%) during double-blind treatment; none were considered related to treatment. Conclusions: These findings indicate that treatment with fentanyl sublingual spray results in effective relief of BTCP, with a rapid onset of action, and is well tolerated.

Single-dose pharmacokinetics of fentanyl sublingual spray and oral transmucosal fentanyl citrate in healthy volunteers: a randomized crossover study.

BACKGROUND Fentanyl sublingual spray (FSS) is a novel fentanyl formulation recently developed for the treatment of breakthrough cancer pain, which is characterized by a fast onset and a relatively short duration. OBJECTIVE To compare rate of absorption and systemic bioavailability between FSS and oral transmucosal fentanyl citrate (OTFC) in healthy volunteers. METHODS This randomized 3-way crossover study involved 29 healthy volunteers (25 men and 4 women; mean age, 35 years) who received single doses of FSS (400 μg), OTFC (400 μg), and intravenous fentanyl citrate (100 μg) separated by washout periods of ≥7 days. Oral naltrexone was given to minimize potential adverse effects of fentanyl. Plasma fentanyl concentrations were measured for 36 hours after each dose for the calculation of pharmacokinetic parameters. RESULTS Mean Cmax values of fentanyl were higher with FSS versus OTFC (0.81 ng/mL vs 0.61 ng/mL) and were attained more quickly; the median Tmax was 1.5 hours with FSS and 2.0 hours with OTFC (P < 0.05). Furthermore, potentially effective fentanyl concentrations were achieved more quickly with FSS than with OTFC. Five and 10 minutes after administration, mean plasma concentrations were 19.0% and 53.7% of Cmax with FSS, respectively, compared with levels below the lower limit of assay quantification and 6.1%, respectively, with OTFC. Plasma concentrations of fentanyl at 10 minutes with FSS were equivalent to those with OTFC at 60 minutes. The Cmax and AUCs were approximately 33% to 36% greater with FSS than with OTFC, and the 90% CIs of the geometric mean ratios for each parameter fell outside the bioequivalence range of 80% to 125%. Systemic bioavailability was also greater with FSS than with OTFC (approximately 76% vs 51%). All 3 fentanyl treatments were well tolerated. All reported adverse events were mild and consistent with those previously reported in healthy volunteers receiving transmucosal fentanyl with naltrexone, and none occurred in >2 participants during any treatment period. CONCLUSIONS Absorption of fentanyl in this study was faster and bioavailability was greater with FSS than with OTFC. The pharmacokinetic profile of the sublingual spray closely matches the duration of onset to pain intensity in a breakthrough cancer pain episode. These findings suggest that FSS is appropriate for the treatment of breakthrough cancer pain. ClinicalTrials.gov identifier: NCT01780233.

Patient Satisfaction with Fentanyl Sublingual Spray in Opioid-Tolerant Patients with Breakthrough Cancer Pain

Breakthrough cancer pain (BTCP) is associated with decreased satisfaction with around‐the‐clock opioid therapy. This analysis examined patient satisfaction with fentanyl sublingual spray for BTCP during the open‐label titration period of a randomized, placebo‐controlled study.

Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl

AIM To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). METHODS Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). RESULTS Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). CONCLUSION FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.

Effective Dose Titration of Fentanyl Sublingual Spray in Patients With Breakthrough Cancer Pain.

To further describe effective dose titration of fentanyl sublingual spray to treat breakthrough cancer pain (BTCP) during the 26‐day open‐label titration phase of a phase 3, randomized, double‐blind, placebo‐controlled study.

Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers

Background Dronabinol, a pharmaceutical Δ-9-tetrahydrocannabinol, was originally developed as an oral capsule. This study evaluated the bioavailability of a new formulation, dronabinol oral solution, versus a dronabinol capsule formulation. Methods In an open-label, four-period, single-dose, crossover study, healthy volunteers were randomly assigned to one of two treatment sequences (T-R-T-R and R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsule) under fasted conditions, with a minimum 7-day washout period between doses. Analyses were performed on venous blood samples drawn 15 minutes to 48 hours postdose, and dronabinol concentrations were assayed by liquid chromatography–tandem mass spectrometry. Results Fifty-one of 52 individuals had pharmacokinetic data for analysis. The 90% confidence interval of the geometric mean ratio (oral solution/capsule) for dronabinol was within the 80%–125% bioequivalence range for area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration (AUC0–t) and AUC from time zero to infinity (AUC0–∞). Maximum plasma concentration was also bioequivalent for the two dronabinol formulations. Intraindividual variability in AUC0–∞ was >60% lower for dronabinol oral solution 4.25 mg versus dronabinol capsule 5 mg. Plasma dronabinol concentrations were detected within 15 minutes postdose in 100% of patients when receiving oral solution and in <25% of patients when receiving capsules. Conclusion Single-dose dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsule 5 mg under fasted conditions. Dronabinol oral solution formulation may provide an easy-to-swallow administration option with lower intraindividual variability as well as more rapid absorption versus dronabinol capsules.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers

Abstract Objective: Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. Research design: Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. Results: Fifty participants (19−53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27–0.60 h post-dose for fentanyl sublingual spray. Peak (Cmax) and total (AUC0–t, AUC0–∞) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. Conclusions: Overall, single-dose fentanyl sublingual spray (100–800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses between 400–800 mcg may be administered in settings with nasal cannula oxygenation.

Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

199 Background: Dronabinol, a pharmaceutical tetrahydrocannabinol (THC), capsule is approved for anorexia associated with weight loss in patients with AIDS and for cancer chemotherapy-induced nausea/vomiting in patients with inadequate response to conventional antiemetic therapy. Food effects on absorption and bioavailability of a new dronabinol oral solution was compared with marketed capsules. METHODS In an open-label, single-dose, 3-period crossover study, healthy volunteers were randomized to receive dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted), after a 7-day washout period. Doses were administered under a fasted (overnight) or fed state (high-fat/calorie meal 30 minutes pre-dose). Plasma pharmacokinetics was evaluated for dronabinol and the major metabolite, 11-OH-Δ9-THC. RESULTS Pharmacokinetic data of 54 volunteers were analyzed. In the fed state, initial dronabinol absorption was rapid with oral solution versus capsules (mean Tlag, 0.15 vs 2.02 h), and 100% and 15% of volunteers receiving oral solution and capsules, respectively, had detectable plasma dronabinol levels 30 minutes post-dose. Inter-individual variability in plasma dronabinol concentrations during early absorption was less with oral dronabinol solution (%CV: 82.79%, 83.94%, and 90.68%) versus capsules (%CV: 318.54%, 250.33%, and 182.01%) observed at 0.5, 1, and 2 h, respectively, after dosing. Food increased mean AUC0-t similarly for dronabinol oral solution and capsules, versus capsules with fasting, increasing exposure to oral solution and capsules 2.1- to 2.4-fold. Mean Tmax was similarly delayed for dronabinol oral solution (7.7 h) and capsules (5.6 h) with food relative to fasting (1.7 h). On the basis of 11-OH-Δ9-THC plasma levels, AUC0-t up to 48 h postdose and AUC0-inf were found to be similar for the oral solution and capsules under fed conditions. CONCLUSIONS An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients given its rapid absorption and lower inter-individual variability compared with dronabinol capsules. CLINICAL TRIAL INFORMATION NCT01448772.

A single-dose comparative bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

198 Background: The capsule formulation of dronabinol, a pharmaceutical tetrahydrocannabinol (THC), is approved for anorexia associated with weight loss in patients with AIDS and for cancer chemotherapy-associated nausea/vomiting in patients with inadequate response to conventional antiemetics. A new oral formulation (i.e., dronabinol solution) was evaluated in a bioequivalence study versus currently marketed dronabinol capsules. METHODS In an open-label, 2-treatment, 2-sequence, 4-period, single-dose crossover study, healthy volunteers were randomized to receive 1 of 2 treatment sequences (T-R-T-R or R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsules). Dosing occurred after an overnight fast, with a minimum 7-day washout period between treatment periods. A validated liquid chromatography-tandem mass spectrometry method was used to determine plasma concentrations of dronabinol and the primary metabolite 11-OH-Δ9-THC. RESULTS Fifty-one of 52 enrollees had pharmacokinetic data for analysis. Mean pharmacokinetics were (oral solution vs capsule): Cmax (2.0 vs 2.4 ng/mL), median Tmax (1.0 vs 1.5 h), AUC0-∞ (3.8 vs 4.1 h∙ng/mL), and t1/2 (5.6 vs 3.1 h). The 2 formulations were bioequivalent with respect to maximum plasma concentration (Cmax; reference-scaled criteria) and area under the plasma concentration-time curve (from time zero to last measurable concentration and from time zero to infinity [AUC0-∞]; average bioequivalence) of dronabinol. The data for the 11-OH-Δ9-THC metabolite provide further support for the bioequivalence of the 2 products. Post hoc analysis demonstrated that all volunteers (100%) had detectable plasma dronabinol concentrations at 15 min with the oral solution compared with < 25% of volunteers for the capsules. Intra-individual variability was lower with oral solution versus capsules (for AUC0-∞, 13.5% vs 36.8%, respectively). CONCLUSIONS Dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsules 5 mg, and exhibited quicker onset of detectable levels and lower intra-individual variability in comparison with dronabinol capsules 5 mg. CLINICAL TRIAL INFORMATION NCT01448772.

Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl.

175 Background: Sublingual fentanyl spray is indicated for the treatment of breakthrough cancer pain (BTCP) in opioid-tolerant patients receiving around-the-clock (ATC) opioids. This post hoc analysis characterized patients receiving ATC transdermal fentanyl patch (TFP) who also received fentanyl sublingual spray for BTCP during a phase 3, randomized, placebo-controlled trial. METHODS Opioid-tolerant adults (n=130) receiving ATC opioids for baseline pain, with 1 to 4 episodes/day of BTCP, were enrolled in a 26-day open-label titration period and received fentanyl sublingual spray. Patients who successfully titrated to a stable, effective dose (100-1,600 mcg) of fentanyl sublingual spray entered a 26-day double-blind period. Patient satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM). Adverse events (AEs) were monitored throughout the study. RESULTS Of the 50 patients (mean age, 50 years) who were on ATC TFP at baseline, most were male (58%) and white (90%) with a mean of 2.4 BTCP episodes/day. The most common types of cancer were reproductive (22%), head and neck (14%), and lung (8%). The percentage of patients in each cancer stage was 0/I (14%), II (10%), III/IV (48%), or unknown/not applicable (28%). Thirty-two of 50 patients (64%) achieved an effective dose of sublingual fentanyl spray and entered the double-blind period. In the 32 patients, the mean baseline TFP dose at the beginning of double-blind period was 81.4 mcg. The mean daily number of BTCP episodes during the 26-day double-blind period was 2.3 (range, 1-5). Mean TSQM scores at baseline and end of the titration period, respectively, were as follows: effectiveness, 49.0 vs 78.3; side effects, 65.0 vs 94.4; convenience, 61.6 vs 73.8; and global satisfaction, 49.3 vs 72.8. The effective dose of fentanyl sublingual spray only moderately correlated with the mean TFP dose (r=0.4; P=0.03). During the double-blind period, 19 of 32 patients (59%) reported AEs; the most common AEs were nausea (9%) and peripheral edema (9%). No opioid overdoses were reported. CONCLUSIONS The findings support that fentanyl sublingual spray relieves BTCP and is well tolerated in most patients receiving ATC transdermal fentanyl. CLINICAL TRIAL INFORMATION NCT00538850.