Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Camurus AB, Ideon Science Park, SE-223 70 Lund, Sweden Phone: +800 2577 2577
Pharmacotherapeutic group: Other nervous system drugs, drugs used in opioid dependence
ATC code: N07BC01
Buprenorphine is an opioid partial agonist/antagonist which binds to the μ (mu) 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 illicit opioids for patients with opioid dependence.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.
The efficacy and safety of Buvidal in the treatment of opioid dependence were established in a pivotal phase 3, randomised, double-blind, double-dummy, active-controlled, flexible-dose study in patients with moderate to severe opioid dependence. In this study, 428 patients were randomised to one of two treatment groups. Patients in the Buvidal group (n=213) received weekly injections (16 mg to 32 mg) during the first 12 weeks followed by monthly injections (64 mg to 160 mg) during the last 12 weeks, plus daily doses of sublingual placebo tablets during the complete treatment period. Patients in the sublingual buprenorphine/naloxone group (n=215) received weekly placebo injections during the first 12 weeks and monthly placebo injections during the last 12 weeks, plus daily sublingual buprenorphine/naloxone tablets during the complete treatment period (8 mg to 24 mg during the first 12 weeks and 8 mg to 32 mg during the last 12 weeks). During the 12 weeks with monthly injections, patients in both groups could receive one additional 8 mg weekly Buvidal dose per month, if needed. Patients attended 12 weekly visits during the first 12 weeks and 6 visits during the last 12 weeks (3 scheduled monthly visits and 3 random urine toxicology visits). At each visit, efficacy and safety outcome measures were assessed.
Of the 428 randomised patients, 69.0% (147/213) of the patients in the Buvidal treatment group and 72.6% (156/215) of the patients in the sublingual buprenorphine/naloxone treatment group completed the 24-week treatment period. The study met the primary endpoint of non-inferiority in mean percentage of urine samples negative for illicit opioids during treatment weeks 1 to 24 for the Buvidal group compared with the sublingual buprenorphine/naloxone group (Table 4).
Superiority of Buvidal versus sublingual buprenorphine/naloxone was met (pre-specified test order) for the secondary endpoint cumulative distribution function (CDF) for percentage of opioid-negative urine samples during treatment weeks 4 to 24 (Table 3).
Table 3. Efficacy variables in a pivotal phase 3, randomised, double-blind, doubledummy, active-controlled, flexible-dose study in patients with moderate to severe opioid dependence:
| Efficacy variable | Statistic | Buvidal | SL BPN/NX | Treatment difference ()a (95 CI) | P-value |
|---|---|---|---|---|---|
| Percentage of urine samples negative for illicit opioids | N | 213 | 215 | ||
| LS mean (%)(SE) | 35.1 (2.48) | 28.4 (2.47) | 6.7 | <0.001 | |
| 95% CI | 30.3 – 40.0 | 23.5 – 33.3 | -0.1 – 13.6 | ||
| CDF of percentage of urine samples negative for illicit opioids over weeks 4-24 | N | 213 | 215 | ||
| Median | 26.7 | 6.7 | - | 0.008b |
CDF = cumulative distribution function, CI = confidence interval, LS = least squares; SE = standard error, SL BPN/NX = sublingual buprenorphine/naloxone
a Difference = Buvidal – SL BPN/NX.
b The p-value was for superiority
A long-term, open-label, phase 3 safety study with flexible dosing of weekly and monthly Buvidal for 48 weeks was conducted. The study enrolled a total of 227 patients with moderate to severe opioid dependence, of which 190 patients were switched from sublingual buprenorphine (with or without naloxone), and 37 patients were new to buprenorphine treatment. During the 48-week treatment period, patients could be transitioned between weekly and monthly injections with Buvidal and between doses (8 mg to 32 mg weekly Buvidal and 64 mg to 160 mg monthly Buvidal) according to the physician’s clinical judgement.
For patients who were switched from sublingual buprenorphine, the percentage of patients with illicit opioid-negative urine samples was 78.8% at baseline and 84.0% at the end of the 48-week treatment period. For the new-to-treatment patients, the percentage of patients with illicit opioid-negative urine samples was 0.0% at baseline and 63.0% at the end of the 48-week treatment period. Overall, 156 patients (68.7%) completed the 48-week treatment period.
After injection, the buprenorphine plasma concentration increases with a median time to maximum plasma concentration (tmax) of about 24 hours. Buvidal has complete absolute bioavailability. Steadystate exposure is reached at the fourth weekly dose. Dose-proportional increases in exposure are observed in the dose interval 8 mg to 32 mg.
The apparent volume of distribution for buprenorphine is approximately 1900 L. Buprenorphine is approximately 96% protein-bound, primarily to alpha and beta globulin.
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a µ-opioid agonist with weak intrinsic activity.
Subcutaneous administration of Buvidal results in significantly lower plasma concentrations of norbuprenorphine metabolite compared to administration of sublingual buprenorphine, due to avoidance of first-pass metabolism.
Elimination of buprenorphine from Buvidal is release-rate limited with a terminal half-life ranging from 3 to 5 days.
Buprenorphine is primarily eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the remainder being eliminated in the urine. Total clearance of buprenorphine is approximately 68 L/h.
No pharmacokinetic data in elderly patients (> 65 years) are available.
Renal elimination plays a relatively small role (≈30%) in the overall clearance of buprenorphine. No dose modification based on renal function is required, but caution is recommended when dosing subjects with severe renal impairment (see sections 4.2 and 4.4).
Table 4 summarises the results of a clinical study in which exposure to buprenorphine was determined following administration of a buprenorphine/naloxone 2.0/0.5 mg sublingual tablet in healthy subjects and in subjects with different degrees of hepatic impairment.
Table 4. Effect of hepatic impairment (change relative to healthy subjects) on pharmacokinetic parameters of buprenorphine following sublingual buprenorphine/naloxone administration (2.0/0.5 mg) in healthy subjects, and in subjects with varied degrees of hepatic impairment:
| Pharmacokinetic 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 |
Overall, buprenorphine plasma exposure increased approximately 3-fold in subjects with severely impaired hepatic function (see sections 4.2, 4.3 and 4.4).
No pharmacokinetic data in paediatrics (less than 18 years) are available. Simulated buprenorphine exposure data in adolescents aged 16 years show lower Cmax and AUC compared to observed values in adults for weekly and monthly Buvidal.
Acute toxicity of buprenorphine was determined in mice and rats following oral and parenteral (intravenous, intraperitoneal) administration. Undesirable effects were based on the known pharmacological activity of buprenorphine.
Buprenorphine showed low tissue and biochemical toxicities when beagles were dosed subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months.
Teratology and reproduction toxicity studies in rats and rabbits by intramuscular administration concluded that buprenorphine is not embryotoxic or teratogenic and has no marked effects on weaning potential. In rats there were no adverse effects on fertility of general reproductive function. Chronic toxicity studies in rat and dog of the vehicle used for Buvidal revealed no special hazard for humans.
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