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Pharmacology: Pharmacodynamics: Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
The analgesic effects of fentanyl are related to its plasma level. In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of Fentora should be individually titrated to achieve the desired effect (see Dosage & Administration).
All opioid µ-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy as these patients will develop tolerance to respiratory depressant effects.
The safety and efficacy of Fentora have been evaluated in patients taking the drug at the onset of the breakthrough pain episode. Pre-emptive use of Fentora for predictable pain episodes was not investigated in the clinical trials. Two double-blind, randomized, placebo-controlled crossover studies have been conducted involving a total of 248 patients with BTP and cancer who experienced on average 1 to 4 episodes of BTP per day while taking maintenance opioid therapy. During an initial open-label phase, patients were titrated to an effective dose of Fentora. Patients who identified an effective dose entered the double-blind phase of the study. The primary efficacy variable was the patient's assessment of pain intensity. Patients assessed pain intensity on an 11-point scale. For each BTP episode, pain intensity was assessed prior to and at several time points after treatment.
Sixty-seven percent of the patients were able to be titrated to an effective dose.
In the pivotal clinical study (study 1), the primary endpoint was the average sum of differences in pain intensity scores from dosing to 60 minutes, inclusive (SPID60), which was statistically significant compared to placebo (p<0.0001) (see Figure 1).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageIn the second pivotal study (study 2), the primary endpoint was SPID30, which was also statistically significant compared to placebo (p<0.0001) (see Figure 2).
Statistically significant improvement in pain intensity difference was seen with Fentora versus placebo as early as 10 minutes in Study 1 and as early as 15 minutes (earliest time point measured) in Study 2. These differences continued to be significant at each subsequent time point in each individual study.
Pharmacokinetics: General introduction: Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more slowly by the conventional gastrointestinal route. It is subject to first-pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.
Fentora employs a delivery technology which utilises an effervescent reaction which enhances the rate and extent of fentanyl absorbed through the buccal mucosa. Transient pH changes accompanying the effervescent reaction may optimise dissolution (at a lower pH) and membrane permeation (at a higher pH).
Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not affect early systemic exposure to fentanyl. A comparison study between one 400 mcg Fentora tablet administered either buccally (i.e., between the cheek and the gum) or sublingually met the criteria of bioequivalence.
The effect of renal or hepatic impairment on the pharmacokinetics of Fentora has not been studied.
Absorption: Following oromucosal administration of Fentora, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Fentora is largely the result of an initial rapid absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after oromucosal administration. Approximately 50% of the total dose administered is rapidly absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and slowly absorbed from the gastrointestinal tract. About 30% of the amount swallowed (50% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.
The main pharmacokinetic parameters are shown in the following table (see Table 1).
Click on icon to see table/diagram/imageIn pharmacokinetic studies that compared the absolute and relative bioavailability of Fentora and oral transmucosal fentanyl citrate (OTFC), the rate and extent of fentanyl absorption in Fentora demonstrated exposure that was between 30% to 50% greater than that for oral transmucosal fentanyl citrate. If switching from another oral fentanyl citrate product, independent dose titration with Fentora is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered. (See Figure 3.)
Click on icon to see table/diagram/imageDifferences in exposure with Fentora were observed in a clinical study with patients with grade 1 mucositis. Cmax and AUC0-8 were 1% and 25% higher in patients with mucositis compared to those without mucositis, respectively. The differences observed were not clinically significant.
Distribution: Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. After buccal administration of Fentora, fentanyl undergoes initial rapid distribution that represents an equilibration of fentanyl between plasma and the highly perfused tissues (brain, heart and lungs). Subsequently, fentanyl is redistributed between the deep tissue compartment (muscle and fat) and the plasma.
The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.
Biotransformation: The metabolic pathways following buccal administration of Fentora have not been characterised in clinical studies. Fentanyl is metabolised in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.
Elimination: Following the intravenous administration of fentanyl, less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.
Following the administration of Fentora, the terminal elimination phase of fentanyl is the result of the redistribution between plasma and a deep tissue compartment. This phase of elimination is slow, resulting in a median terminal elimination half-life t1/2 of approximately 22 hours following buccal administration of the effervescent formulation and approximately 18 hours following intravenous administration. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
Linearity/non-linearity: Dose proportionality from 100 micrograms to 1000 micrograms has been demonstrated.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.
Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period of organogenesis.
In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300 mcg/kg/day, s.c.) and is considered secondary to the sedative effects of fentanyl in animal studies.
In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.
Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown.
