Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Indivior Europe Limited, 27 Windsor Place, Dublin 2, D02 DK44, Ireland
Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders
ATC code: N07BC51
Buprenorphine is an opioid partial agonist/antagonist which binds to the µ and κ (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the µ-opioid receptors which, over a prolonged period, might minimise the need of addicted patients for drugs.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.
Naloxone is an antagonist at µ-opioid receptors. When administered orally or sublingually in usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological effect because of its almost complete first pass metabolism. However, when administered intravenously to opioid-dependent persons, the presence of naloxone in Suboxone produces marked opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.
Efficacy and safety data for buprenorphine/naloxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of buprenorphine/naloxone, buprenorphine and placebo followed by a 48 week safety study of buprenorphine/naloxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either buprenorphine/naloxone 16 mg per day, 16 mg buprenorphine per day or placebo. For subjects randomized to either active treatment, dosing began with 8 mg of buprenorphine on Day 1, followed by 16 mg (two 8 mg) of buprenorphine on Day 2. On Day 3, those randomized to receive buprenorphine/naloxone were switched to the combination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. The primary study comparison was to assess the efficacy of buprenorphine and buprenorphine/naloxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine/naloxone versus placebo (p<0.0001) and buprenorphine versus placebo (p<0.0001).
In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution versus a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg/day of buprenorphine/naloxone), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually. Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.
Buprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation and glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with increasing sublingual dose of buprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose-proportional.
Table 2. Buprenorphine Mean Pharmacokinetic Parameters:
| Pharmacokinetic Parameter | Suboxone 4 mg | Suboxone 8 mg | Suboxone 16 mg |
|---|---|---|---|
| Cmax ng/ml | 1.84 (39) | 3.0 (51) | 5.95 (38) |
| AUC0-48 hour ng/ml | 12.52 (35) | 20.22 (43) | 34.89 (33) |
Table 3. Changes in pharmacokinetic parameters for Suboxone film administered sublingually or buccally in comparison to Suboxone sublingual tablet:
| 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 × 2 mg/0.5 mg | Cmax | 22% | 25% | - | Cmax | - | - | - |
| AUC0-last | - | 19% | - | AUC0-last | - | - | - | |
| 2 × 2 mg/0.5 mg | Cmax | - | 21% | 21% | Cmax | - | 17% | 21% |
| AUC0-last | - | 23% | 16% | AUC0-last | - | 22% | 24% | |
| 1 × 8 mg/2 mg | Cmax | 28% | 34% | - | Cmax | 41% | 54% | - |
| AUC0-last | 20% | 25% | - | AUC0-last | 30% | 43% | - | |
| 1 × 12 mg/3 mg | Cmax | 37% | 47% | - | Cmax | 57% | 72% | 9% |
| AUC0-last | 21% | 29% | - | AUC0-last | 45% | 57% | - | |
| 1 × 8 mg/2 mg plus 2 × 2 mg/0.5 mg | Cmax | - | 27% | 13% | Cmax | 17% | 38% | 19% |
| AUC0-last | - | 23% | - | AUC0-last | - | 30% | 19% | |
Note 1. '– 'represents no change when the 90 % confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit.
Note 2. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to the 2 mg/0.5 mg strength film and has the same size as the 2 × 2 mg/0.5 mg film strength.
The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).
Buprenorphine is highly lipophilic, which leads to rapid penetration of the blood-brain barrier. Buprenorphine is approximately 96 % protein bound, primarily to alpha and beta globulin.
Buprenorphine is primarily metabolised through N-dealkylation by liver microsomal CYP3A4. The parent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequent glucuronidation. Norbuprenorphine binds to opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine/naloxone.
Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours. Buprenorphine is excreted in the faeces (~70%) by biliary excretion of the glucuroconjugated metabolites, the rest (~30%) being excreted in the urine.
Buprenorphine Cmax and AUC increased in a linear fashion with the increasing dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional.
Following sublingual administration of buprenorphine/naloxone, plasma naloxone concentrations are low and decline rapidly. Naloxone mean peak plasma concentrations were too low to assess doseproportionality.
Naloxone has not been found to affect the pharmacokinetics of buprenorphine, and both buprenorphine sublingual tablets and buprenorphine/naloxone sublingual film deliver similar plasma concentrations of buprenorphine.
Naloxone is approximately 45 % protein bound, primarily to albumin.
Naloxone is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine. Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide, as well as N-dealkylation and reduction of the 6-oxo group.
Naloxone is excreted in the urine, with a mean half-life of elimination from plasma ranging from 0.9 to 9 hours.
No pharmacokinetic data in elderly patients are available.
Renal elimination plays a relatively small role (~30%) in the overall clearance of buprenorphine/naloxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (see section 4.3).
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study.
Table 4 summarises the results from a clinical trial in which the exposure of buprenorphine and naloxone was determined after administering a buprenorphine/naloxone 2.0/0.5 mg sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.
Table 4. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine and naloxone following Suboxone administration (change relative to healthy subjects):
| PK Parameter | Mild Hepatic Impairment (Child-Pugh Class A) (n=9) | Moderate Hepatic Impairment (Child-Pugh Class B) (n=8) | Severe Hepatic Impairment (Child-Pugh Class C) (n=8) |
|---|---|---|---|
| Buprenorphine | |||
| Cmax | 1.2-fold increase | 1.1-fold increase | 1.7-fold increase |
| AUClast | Similar to control | 1.6-fold increase | 2.8-fold increase |
| Naloxone | |||
| Cmax | Similar to control | 2.7-fold increase | 11.3-fold increase |
| AUClast | 0.2-fold decrease | 3.2-fold increase | 14.0-fold increase |
Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function, while naloxone plasma exposure increased 14-fold with severely impaired hepatic function.
The combination of buprenorphine and naloxone has been investigated in acute and repeated dose (up to 90 days in rats) toxicity studies in animals. No synergistic enhancement of toxicity has been observed. Undesirable effects were based on the known pharmacological activity of opioid agonist and/or antagonistic substances.
The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was not mutagenic in a bacterial mutation assay (Ames test) and was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an intravenous micronucleus test in the rat.
Reproduction studies by oral administration of buprenorphine: naloxone (ratio 1:1) indicated that embryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dose studied represented exposure multiples of 1x for buprenorphine and 5x for naloxone at the maximum human therapeutic dose calculated on a mg/m² basis. No developmental toxicity was observed in rabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats or rabbits. A peri-postnatal study has not been conducted with buprenorphine/naloxone; however, maternal oral administration of buprenorphine at high doses during gestation and lactation resulted in difficult parturition (possible as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.
Dietary administration of buprenorphine/naloxone in the rat at dose levels of 500 ppm or greater produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (estimated exposure approximately 2.4x for buprenorphine at a human dose of 24 mg buprenorphine/naloxone based on AUC, plasma levels of naloxone were below the limit of detection in rats) had no adverse effect on fertility in females.
A carcinogenicity study with buprenorphine/naloxone was conducted in rats at doses of 7 mg/kg/day, 30 mg/kg/day and 120 mg/kg/day, with estimated exposure multiples of 3 times to 75 times, based on a human daily sublingual dose of 16 mg calculated on a mg/m² basis. Statistically significant increases in the incidence of benign testicular interstitial (Leydig’s) cell adenomas were observed in all dosage groups.
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