Buprenorphine and Naloxone (Page 10 of 15)
Cardiac Electrophysiology
Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec.
12.3 Pharmacokinetics
Absorption
In several pharmacokinetic studies following the administration of different dosages, a dose of one or two of the 2 mg/0.5 mg buprenorphine and naloxone sublingual films administered sublingually or buccally showed comparable relative bioavailability to the same total dose of buprenorphine and naloxone sublingual tablets. In contrast, one 8 mg/2 mg and one 12 mg/3 mg buprenorphine and naloxone sublingual films administered sublingually or buccally showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total dose of buprenorphine and naloxone sublingual tablets. A combination of one 8 mg/2 mg and two 2 mg/0.5 mg buprenorphine and naloxone sublingual films (total dose of 12 mg/3 mg) administered sublingually showed comparable relative bioavailability to the same total dose of buprenorphine and naloxone sublingual tablets, while buccally administered buprenorphine and naloxone sublingual films showed higher relative bioavailability. Table 5, below, illustrates the relative increase in exposure to buprenorphine and naloxone associated with buprenorphine and naloxone sublingual films compared to buprenorphine and naloxone sublingual tablets, and shows the effect of route of administration [see Dosage and Administration (2.9, 2.10)].
Across relevant pharmacokinetic studies, the pharmacokinetic parameters and exposures derived from the buccal and sublingual administrations of buprenorphine and naloxone sublingual film were comparable to one another.
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence intervals for the geometric mean ratios of the C max and AUC 0-last values are within the 80% to 125% limit. 3. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 x 2 mg/0.5 mg film strength. | ||||||||
Dosage | PK Parameter | Increase in Buprenorphine | PK Parameter | Increase in Naloxone | ||||
Film Sublingual Compared to Tablet Sublingual | Film Buccal Compared to Tablet Sublingual | Film Buccal Compared to Film Sublingual | Film Sublingual Compared to Tablet Sublingual | Film Buccal Compared to Tablet Sublingual | Film Buccal Compared to Film Sublingual | |||
1 x 2 mg/0.5 mg | C max | 22% | 25% | – | C max | – | – | – |
AUC 0-last | – | 19% | – | AUC 0-last | – | – | – | |
2 x 2 mg/0.5 mg | C max | – | 21% | 21% | C max | – | 17% | 21% |
AUC 0-last | – | 23% | 16% | AUC 0-last | – | 22% | 24% | |
1 x 8 mg/2 mg | C max | 28% | 34% | – | C max | 41% | 54% | – |
AUC 0-last | 20% | 25% | – | AUC 0-last | 30% | 43% | – | |
1 x 12 mg/3 mg | C max | 37% | 47% | – | C max | 57% | 72% | 9% |
AUC 0-last | 21% | 29% | – | AUC 0-last | 45% | 57% | – | |
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg | C max | – | 27% | 13% | C max | 17% | 38% | 19% |
AUC 0-last | – | 23% | – | AUC 0-last | – | 30% | 19% | |
1 x 16 mg/4 mg film | C max | 34% | 29% | 7% | C max | 44% | 46% | 9% |
AUC 0-last | 32% | – | – | AUC 0-last | 49% | 36% | 3% |
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