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FENTORA® (fentanyl buccal tablets) - Pharmacokinetics
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IssuesKey Educational ConceptSupportive Documentation
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PharmacokineticsSystemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100-800-mcg dose range. FENTORA PI
Darwish et al. Clin Therapeutics 2006;28 (5): 707-714.
Darwish et al. Clin Pharmacokinet 2005; 44 (12): 1279-1286 (Study 99-18)
Blick et al. Drugs 2006; 66 (18): 2387-2393		Darwish 2006Darwish 2005Blick 2006
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AbsorptionFENTORA leads to earlier and greater systemic exposure of fentanyl than Actiq resulting from increased bioavailability. Caution must be exercised when switching patients from one product to another. FENTORA PI
Darwish et al, J Clin Pharmacol 2007; 47:343-350.		Darwish 2007
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BioavailabilityThe absolute bioavailability of FENTORA is 65% vs. 47% with Actiq. 48% of the total dose vs. 22% with Actiq is absorbed transmucosally, the remaining half is swallowed and undergoes more prolonged absorption from the GI tract.Darwish et al. Clin Therapeutics 2006;28(5):715-724. (Study 99-14)Darwish 2006
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PK parameters for FENTORA 400 mcg and Actiq 400 mcg (dose normalized) [Table 1, Figure 1 in PI]Results are based on venous blood samples.
Actiq was dose adjusted (800 mcg to 400 mcg). 		FENTORA PI
Darwish et al, J Clin Pharmacol 2007; 47:343-350.		Darwish 2007
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Tmax (minute)46.8 and 90.8
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Cmax (ng/ml)1.02 and 0.63
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AUC0-tmax (ng/ml)0.4 and 0.14
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AUC0-inf (ng/ml)6.48 and 4.79
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Dwell timeDwell time (defined as the length of time that a tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.FENTORA PI, Darwish et al, Expert Opin Pharmacother 2007;9(13):2011-2016.Darwish 2007
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MucositisMinimal differences were noted in pharmacokinetic parameters with a trend towards higher AUC0-8 in patients with Grade 1 mucositis compared to those without mucositis. However, all estimated pharmacokinetic parameters had large inter-patient variability, therefore, this along with the small sample size should be considered when interpreting the results of this study. The PI does not recommend dosage adjustment in patients with Grade 1 mucositis. FENTORA PI, Darwish et al, Clin Drug Invest 2007;(9):605-611.Darwish 2007
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Sublingual absorption Criteria for bioequivalence were met for both Cmax and AUC∞ for the sublingual and buccal sites of tablet placement.Darwish et al. Clin Drug Invest 2008;28(1):1-7.Darwish 2008
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FENTORA tablet equivalency: 1 x 400 mcg vs. 4 x 100 mcg They are not bioequivalent with a higher AUC and Cmax reported with the four 100-mcg tablets although the differences were relatively small. The clinical impact has not been evaluated. FENTORA PI, Darwish et al, Clin Pharmacokinet 2006;48(8):843-850.Darwish 2006
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DistributionFentanyl is highly lipophilic and is thus well distributed beyond the vascular system resulting in a large volume of distribution of 25.4 L/Kg. Distribution is rapid to highly perfused tissues (brain, lung, heart), after which fentanyl is rapidly redistributed to deep tissue and plasma (from which it is slowly eliminated) resulting in plasma concentrations that quickly fall below therapeutic levels. FENTORA PI, Darwish et al. Clin Therapeutics 2006;28(5):707-714., Medical Information Response (Data on File). Darwish 2006
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Protein bindingThe plasma protein binding of fentanyl is 80-85% FENTORA PIFentora PI
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MetabolismFentanyl is primarily metabolized in the liver and to a lesser extent in the intestinal mucosa to norfentanyl, an inactive metabolite, by cytochrome P450 3A4. This should be considered when coadministering FENTORA with inhibitors and inducers of CYP3A4 (see Drug Interactions in Safety tab).FENTORA PIFentora PI
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EliminationFentanyl and it's metabolites are mainly excreted in the urine, >90% is eliminated as metabolites. FENTORA PIFentora PI
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Half-lifeElimination of fentanyl is slow, with a median terminal half-life of approximately 22 hours after multiple doses (12 hours after a single dose). This is consistent with the final phase of prolonged elimination from the deep tissue compartment (see Distribution).FENTORA PIFentora PI
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Steady stateSteady state is reached in 5 days of dosing, consistent with the half-life of fentanyl. At steady state, the systemic exposure is about 2-fold higher compared to that of a single dose of FENTORA. Darwish et al. J Clin Pharmacol 2007;47:56-63.Darwish 2007
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Issues
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Arterial vs. venous blood sampling Significant differences in pharmacokinetic parameters may result from venous and arterial blood sampling of fentanyl following administration of FENTORA. This should be kept in mind when examining the results reported in the Actiq PI which were based on arterial sampling vs. that reported in the FENTORA PI which were based on venous sampling. Darwish et al. Clin Ther 2006;28(5):707-714.Darwish 2006
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After a single buccal dose of FENTORA 400 mcg, early exposure (measured by AUC and Tmax) was more than 2 fold higher in the venous vs. arterial circulation. The mean arterial peak plasma concentrations of fentanyl was 60% higher and occurred 15 minutes earlier than that from venous circulation.
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Onset of AnalgesiaThe onset of analgesia has not been measured however, FENTORA showed significant analgesia as early as 10 minutes for BTP episodes in patients with cancer, chronic low back pain and chronic neuropathic pain. Slatkin et al, J Supportive Onc 2007;5(7):227-334.
Simpson et al, Clin Ther 2007;29(4(:588-601.
Portenoy et al, Clin J Pain 2007;23(1):223-233.		Slatkin 2007
Simpson 2007Portenoy 2007
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Duration of analgesiaFENTORA demonstrated continued analgesia at the last time points for which the degree of pain and pain relief was measured in studies of BTP in patients with cancer, chronic neuropathic and chronic low back pain at 120 minutes. Slatkin et al, J Supportive Onc 2007;5(7):227-334.
Simpson et al, Clin Ther 2007;29(4(:588-601.
Portenoy et al, Clin J Pain 2007;23(1):223-233.		Slatkin 2007Simpson 2007Portenoy 2007
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Relative potency to ActiqThe equivalent dose of FENTORA is approximately two thirds that of Actiq (as demonstrated in Figure depicting similar peak concentrations for 400 mcg of FENTORA and 600 mcg of Actiq). However, the HCP should follow recommendations from the PI for switching patients from Actiq to FENTORA.FENTORA PI
Darwish et al, J Clin Pharmacol 2007; 47:343-350.		Darwish 2007
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