NUMBER OF MEDICINES

Buprenorphine 0.4 mg, 2 mg, 8 mg,
sublingual tablet

Excipient: Lactose monohydrate, mannitol, corn starch, povidone K30, anhydrous citric acid, sodium citrate, magnesium stearate.

White to cream, oval, flat, bevelled-edged tablet with “04” engraved on one side.

INDICATIONS :

Replacement treatment for opioid drug dependence, as part of a comprehensive therapeutic approach to medical, social and psychological care.

The treatment is reserved for adults and adolescents over the age of 15 who volunteer to receive treatment for opioid dependence.

DOSAGE AND METHOD OF ADMINISTRATION

Treatment must be carried out under the supervision of a doctor specialized in the management of opioid dependence/addiction.

Buprenorphine treatment is recommended to be prescribed as part of comprehensive management of opioid dependence.

The result of the treatment depends, on the one hand, on the prescribed dosage and on the other hand, on the associated medico-psychological and socio-educational measures for patient monitoring.

Precautions to take before induction of treatment

Before initiating treatment, the physician should consider the type of opioid dependence (long-acting or short-acting opioids), the time interval since the last opioid intake, and the level of opioid dependence. opioids. To avoid precipitating the onset of a withdrawal syndrome, induction of treatment with buprenorphine should be carried out as soon as objective and obvious signs of withdrawal appear (demonstrated, for example, by a score indicating mild withdrawal to moderate on the validated Clinical Opioid Withdrawal Symptoms Scale (COWS)).

In patients dependent on heroin or short-acting opioids, the first dose of buprenorphine should be taken when the first signs of withdrawal appear but should occur at least 6 hours after the last opioid intake. .

In patients receiving methadone, the methadone dose should be decreased to a maximum dosage of 30 mg/day before initiating buprenorphine treatment. The long half-life of methadone should be taken into account when initiating buprenorphine treatment. The first dose of buprenorphine should only be taken when the first signs of withdrawal appear and usually not less than 24 hours after the last dose of methadone. Buprenorphine may precipitate the onset of withdrawal symptoms in patients dependent on methadone.

Dosage:

Implementation of treatment (induction):

The recommended initial dose for adults and adolescents over 15 years of age is 2 to 4 mg once daily. An additional dose of 2 to 4 mg may be administered on the first day depending on the individual patient's needs. During the initiation phase of treatment, it is recommended to monitor its administration daily to ensure that the tablet is placed correctly under the tongue and to observe the patient's response to treatment, which will allow effective adaptation of the treatment. dose administered according to the clinical effect obtained in the patient.

Dosage adjustment and maintenance treatment:

Following the induction of treatment on day 1, the patient should be stabilized at a maintenance dose over the next few days, gradually adapting the dose administered according to the clinical effect obtained in the patient. Adjustment of the dosage in increments of 2 to 8 mg of buprenorphine depends on the reassessment of the patient's clinical and psychological state and should not exceed the maximum dosage of 24 mg per day of buprenorphine.

Daily delivery of buprenorphine is recommended, particularly during the treatment initiation period. Subsequently and after his condition has stabilized, quantities of medication for several days of treatment may be given to the patient. It is recommended, however, to limit the quantity of medicine dispensed at one time to a maximum of 7 days.

Non-daily administration:

After satisfactory stabilization has been achieved, the frequency of treatment administration may be reduced to every other day by doubling the patient's daily dose. For example, a stabilized patient receiving a daily dose of 8 mg of buprenorphine may receive 16 mg of buprenorphine every other day, with no treatment on intervening days. In some patients, after satisfactory stabilization has been achieved, the frequency of treatment administration may be reduced to 3 administrations per week (e.g. Monday, Wednesday and Friday). The dose on Monday and Wednesday should be equal to twice the patient's daily dose, and the dose on Friday should be equal to three times the patient's daily dose, with no treatment on intervening days. In no case should the dose exceed 24 mg of buprenorphine per day. This dosage may not be suitable for patients requiring a daily dose > 8 mg buprenorphine/day.

Reducing doses and stopping treatment (gradual cessation):

When clinical assessment and the patient's wishes lead to consideration of stopping treatment, this must be done with caution. The decision to stop treatment with buprenorphine after a brief maintenance or stabilization period must be taken as part of overall management. To avoid withdrawal symptoms and possible relapse, in favorable cases, the dose of buprenorphine can be gradually reduced until treatment is stopped. After a period of stabilization deemed satisfactory, if the patient accepts it, the doctor may suggest that the patient gradually reduce their dose of buprenorphine, until the substitution treatment is completely stopped in favorable cases. The provision of sublingual tablets dosed at 0.4 mg, 2 mg and 8 mg respectively allows a gradual reduction in the dosage. During the period of stopping treatment, particular attention will be paid to the risks of relapse.

Special populations

Elderly subjects

The safety and effectiveness of buprenorphine in patients older than 65 years have not been established. No dosage recommendation can be given.

Hepatic insufficiency

A liver test and testing for viral hepatitis are recommended before starting treatment.

The effect of hepatic impairment on the pharmacokinetics of buprenorphine was evaluated in a post-marketing study. Due to the extensive metabolism of buprenorphine, higher plasma levels of buprenorphine are found in patients with hepatic impairment. Systemic exposure is slightly increased in subjects with mild hepatic impairment and no dosage adjustment is considered necessary.

After administration of a single dose of 2 mg, total systemic exposure is significantly increased in subjects with moderate (1.6-fold) and severe (2.8-fold) hepatic impairment compared to healthy subjects. Patients should be monitored for signs and symptoms of toxicity or overdose caused by high levels of buprenorphine. Subutex should be used with caution in patients with moderate hepatic impairment and a reduction in the initial dose and maintenance dose should be considered. Considering high exposure in patients with severe hepatic impairment and possible accumulation after repeated doses, Subutex should not be used in patients with severe hepatic impairment.

Patients with viral hepatitis, under concomitant medical treatment and/or suffering from hepatic dysfunction have a higher risk of accelerated liver damage. An initial liver test and testing for viral hepatitis are recommended before starting treatment. It is recommended to monitor liver function regularly

Renal failure

Dose modification of buprenorphine is generally not necessary in patients with renal impairment. Caution is recommended in patients with severe renal impairment (creatinine clearance < 30 ml/min).

Pediatric population

The safety and effectiveness of buprenorphine in children younger than 15 years have not been established. No data is available.

Due to the lack of data in adolescents (aged 15 to 17 years), these patients should be monitored more closely during treatment.

Administration mode

Sublingual administration: Physicians should inform patients that the sublingual route is the only effective and well-tolerated route for administering this medication. The tablet should be held under the tongue until completely dissolved, which usually takes 5 to 10 minutes. Patients should not swallow or consume food or drink until the tablet has completely dissolved.

One dose consists of Subutex tablets of different strengths, which can be placed under the tongue simultaneously or in two parts; the second part should be placed under the tongue as soon as the tablet(s) from the first part are dissolved. For specific dosing instructions during induction, stabilization and maintenance therapy, refer to the sections above titled “Treatment initiation (induction)” and “Dose adjustment and maintenance therapy”.

Contraindications

• Hypersensitivity to buprenorphine or any of the excipients mentioned


• Children under 15 years old.


• Severe respiratory failure.


• Severe liver failure.


• Acute alcohol poisoning or delirium tremens.


• Combination with methadone, step III opioid analgesics, naltrexone, and nalmefene

Special warnings and precautions for use

Warnings

• This medication is intended exclusively for the treatment of opioid dependence.


• Use in adolescents: Due to the lack of data in adolescents (aged 15 to 17 years), patients in this age group should be more closely monitored during treatment.


• It is recommended that this treatment be prescribed by doctors providing comprehensive therapeutic management of opioid dependence.

Misuse, abuse and misuse

• Like other opioids, legal or illicit, buprenorphine can be misused or abused. The risks of misuse and abuse include overdose, the spread of viral infections or localized and systemic infections transmitted through blood, respiratory depression and liver damage. The misuse of buprenorphine by a person other than the patient for whom the product is intended also risks creating a new category of individuals primarily dependent on this substance; this type of use can also appear when the medicine is distributed directly by the patient for illicit use or when the medicine is stolen, not being kept in a safe place.


• In case of intentional misuse of the drug intravenously, local reactions, sometimes septic (abscesses, cellulitis), potentially serious acute hepatitis and other acute infections, such as pneumonia or endocarditis, have been reported.


• Suboptimal treatment with buprenorphine may indicate patient misuse of the medication, potentially leading to overdose or treatment discontinuation. A patient underdosed on buprenorphine may continue to manage withdrawal symptoms and cravings for opioids, alcohol, or other nooleptics (e.g., benzodiazepines).


• To reduce the risk of misuse, abuse, and misuse, physicians should take appropriate precautions when prescribing and administering buprenorphine, such as avoiding giving prescriptions for multiple refills early on. treatment ; on the other hand, they must carry out follow-up visits to the patient while implementing clinical monitoring adapted to the patient's needs.

Sleep disordered breathing

Opioids can cause sleep-disordered breathing, including central sleep apnea (CSA) and sleep hypoxemia. The risk of SCA increases depending on the dose of opioid used. In patients with SCA, a reduction in the total opioid dose should be considered.

Respiratory depression

• Deaths from respiratory depression have been observed, particularly when buprenorphine has been used in combination with benzodiazepines or when buprenorphine has not been used according to the prescribing information. Deaths have also been reported after concomitant use of buprenorphine and other depressants such as alcohol or other opioids. Administration of buprenorphine to non-opioid-dependent individuals, who are not tolerant to the effects of opioids, may result in potentially fatal respiratory depression.


• This product should be used with caution in patients with asthma or respiratory insufficiency (such as chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory capacity, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis (spinal deformity that can lead to dyspnea).


• Patients with the above physical and/or pharmacological risk factors should be monitored and dose reduction may be considered.


• Buprenorphine can cause severe, life-threatening respiratory depression in children and non-dependent individuals who ingest it accidentally or deliberately. Patients should be warned to keep the blister packs safe, never remove the tablets from the blister pack in advance, keep the blister packs out of the reach of children and other family members, and not take this medicine in front of them. the children. An emergency service should be contacted immediately in the event of accidental ingestion or suspected ingestion.

CNS depression

• Buprenorphine may cause drowsiness, particularly when taken/administered concomitantly with alcohol or with central nervous system depressants (such as benzodiazepines, tranquilizers, sedatives or hypnotics).

Risk of concomitant use of sedatives such as benzodiazepines and related drugs

• Concomitant use of buprenorphine and sedatives such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma, and death. Due to these risks, concomitant prescription of these sedative medications should be reserved for patients for whom there are no therapeutic alternatives. If it is decided to prescribe buprenorphine with sedative medications, the minimum effective dose of the sedative medications should be used and the treatment duration should be as short as possible.


• Patients should be closely monitored so that signs and symptoms of respiratory depression and sedation can be detected. In this regard, it is strongly recommended to inform patients and their caregivers that they should be vigilant for these symptoms.

Serotonin syndrome

• Concomitant administration of Subutex and other serotonergic agents, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, can cause serotonin syndrome, which is a potentially fatal illness.


• If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.


• Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.


• If serotonin syndrome is suspected, a dose reduction or discontinuation of treatment should be considered depending on the severity of the symptoms.

Addiction

• Animal studies and clinical data have demonstrated that chronic administration of buprenorphine, a partial µ-opioid receptor agonist, can cause dependence, although the dependence is less than that caused by chronic administration. by a full agonist (such as morphine).


• Abrupt discontinuation of treatment may lead to a withdrawal syndrome, the first signs of which may appear later.

Hepatitis, liver damage

• Cases of serious acute hepatitis have been reported following misuse, particularly intravenously. This hepatic damage was mainly observed at high doses, and could be due to mitochondrial toxicity. In many cases, the presence of pre-existing mitochondrial dysfunction (genetic disease, liver enzyme abnormalities, hepatitis B or hepatitis C virus infection, alcohol abuse, anorexia, concomitant use of other medications potentially hepatotoxic) and the persistence of drug injections may be responsible for or contribute to liver damage.


• Patients with viral hepatitis, on concomitant medical treatment and/or with hepatic dysfunction are at higher risk of liver damage and these underlying factors should be considered before prescribing buprenorphine and during treatment. treatment.


• If liver damage is suspected, a thorough biological and etiological assessment must be carried out. Depending on the results obtained, treatment may be discontinued with caution to prevent the onset of withdrawal symptoms and avoid a return to illicit drug use. If treatment is continued, liver function should be closely monitored.

Precipitation of opioid withdrawal syndrome

• When initiating treatment with buprenorphine, the physician should take into account the partial agonist profile of buprenorphine and be aware that treatment may precipitate the onset of a withdrawal syndrome in patients dependent on opioids, particularly if treatment is administered less than 6 hours after the last use of heroin or other short-acting opioid, or if administered less than 24 hours after the last use of methadone (consistent with the long half-acting -life of methadone). Patients should be closely monitored when switching from methadone to buprenorphine as withdrawal symptoms have been reported. To avoid precipitating the onset of a withdrawal syndrome, induction of treatment with buprenorphine should be carried out as soon as objective signs of withdrawal appear.


• Withdrawal symptoms may also be associated with underdosing.

Allergic reactions

Cases of acute and chronic hypersensitivity to buprenorphine have been reported in clinical studies and post-marketing. The most common signs and symptoms are: rash, hives and itching. Bronchospasm, angioedema and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of buprenorphine.

Hepatic insufficiency

The effect of hepatic impairment on the pharmacokinetics of buprenorphine was evaluated in a single-dose post-marketing study. Due to the extensive metabolism of buprenorphine, higher plasma levels of buprenorphine are found in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of toxicity or overdose caused by high levels of buprenorphine. Subutex should be used with caution in patients with moderate hepatic impairment. In patients with severe hepatic impairment, the use of buprenorphine is contraindicated.

Renal failure

Renal elimination may be prolonged, as 30% of the administered dose is eliminated via the kidneys. Buprenorphine metabolites accumulate in patients with renal impairment. Caution is recommended in patients with severe renal impairment (creatinine clearance < 30 ml/min).

General warnings relating to the opioid class

• LOpioids can cause orthostatic hypotension.


• Opioids can increase cerebrospinal fluid pressure, which can cause seizures. As with other opioids, caution is advised in patients treated with buprenorphine who have head trauma, intracranial injuries, and increased intracranial pressure or who have a history of seizures.


• Opioid-induced miosis, alterations in the level of consciousness or perception of pain as a symptom of the disease may interfere with the assessment of the patient or complicate the diagnosis or clinical treatment of a concomitant disease.


• Opioids should be used with caution in patients with myxedema, hypothyroidism or adrenocortical insufficiency (e.g. Addison's disease).


• Opioids should be used with caution in patients with hypotension, prostatic enlargement, or urethral stenosis.


• Opioids may cause an increase in intrabileductal pressure and should therefore be used with caution in patients with bile duct dysfunction.


• Opioids should be administered with caution to elderly or debilitated patients.


• The attention of athletes should be drawn to the fact that this specialty contains buprenorphine and that this active ingredient is included on the list of doping substances.


• The following combinations are not recommended with buprenorphine: step II analgesics, ethylmorphine and alcohol.


• Excipients
  
  
  
  • This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) should not take this medicine.
  
  
  • This medicine contains less than 1 mmol (23 mg) sodium per tablet, i.e. that it is essentially “sodium-free”.
  
  
  
  

Interactions with other drugs and other forms of interactions

Contraindicated combinations

• Methadone:

Reduction in the effect of methadone by competitive blockade of receptors, with risk of onset of a withdrawal syndrome.

• Level III opioid analgesics:

In patients using level III analgesics, a reduction in the analgesic effect of the opioid may be observed, through competitive blockade of the receptors, with the risk of the onset of a withdrawal syndrome.

• Naltrexone and nalmefene:

Naltrexone and nalmefene are opioid antagonists that may block the pharmacological effects of buprenorphine. For opioid-dependent patients receiving buprenorphine treatment, co-administration of naltrexone and nalmefene is contraindicated, as naltrexone and nalmefene may precipitate the abrupt onset of prolonged and intense opioid withdrawal symptoms.

Associations not recommended

• Level II analgesics (tramadol, codeine and dihydrocodeine): A reduction in the analgesic effect of the opioid may be observed, by competitive blockade of the receptors, with risk of onset of a withdrawal syndrome.


• Ethylmorphine: In patients using ethylmorphine, a reduction in the analgesic effect of the opioid may be observed, through competitive blockade of receptors, with risk of onset of a withdrawal syndrome.


• Alcohol :
  
  
  
  • Alcohol increases the sedative effect of buprenorphine, which can make driving and using machines dangerous.
  
  
  • Patients should avoid taking buprenorphine with alcoholic beverages or medications containing alcohol.
  
  
  
  

Associations subject to precautions for use

• Sedative medications such as benzodiazepines or related substances

Concomitant use of opioids and sedatives such as benzodiazepines or related substances increases the risk of sedation, respiratory depression, coma and death by increasing the CNS depressant effect. The dose of the sedative and the duration of its concomitant use should be limited. The doses and duration of the combination should be limited as much as possible. Patients should be informed that it is extremely dangerous to self-administer benzodiazepines that have not been prescribed while taking this product and should also be cautioned that they should carefully follow their doctor's instructions when taking this product. they take benzodiazepines.

• Other central nervous system depressants

Other opioid derivatives (e.g. analgesics and cough suppressants), certain antidepressants, sedative H1 antihistamines, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances administered in combination with buprenorphine increase central nervous system depression . Impaired alertness can make driving vehicles and using machines dangerous.

In addition, barbiturates increase the risk of respiratory depression.

• Serotonergic medications, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, because of the risk of serotonin syndrome , which is a potentially fatal disease, is increased.


• CYP3A4 inhibitors

An interaction study between buprenorphine and ketoconazole (a strong CYP3A4 inhibitor) showed an increase in the Cmax and AUC (area under the curve) of buprenorphine (by approximately 50% and 70% respectively) and, to a lesser extent measurement, norbuprenorphine. Patients treated with buprenorphine should be closely monitored and a dose reduction may be necessary if combined with a strong CYP3A4 inhibitor (e.g. protease inhibitors such as ritonavir, nelfinavir or indinavir or antifungals azoles such as ketoconazole, itraconazole, voriconazole or posaconazole).

• CYP3A4 inducers

In a clinical study carried out on healthy volunteers, the combination of buprenorphine with rifampicin or rifabutin showed a decrease of 70% and 35% respectively in plasma concentrations of buprenorphine and the appearance of withdrawal symptoms in 50% of 12 volunteers. . Close monitoring is recommended in patients treated with buprenorphine if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dosage of buprenorphine or CYP3A4 inducers may be adjusted accordingly.

Fertility, pregnancy and breastfeeding

Pregnancy

• Given the available data and the maternal/fetal benefit, buprenorphine can be used during pregnancy. However, an adjustment of the daily dosage may be necessary in order to maintain the effectiveness of the treatment.


• Chronic use of buprenorphine by the mother, whatever the dose, at the end of pregnancy, can lead to a withdrawal syndrome (high-pitched cries, poor food intake, abnormal sleep, irritability, tremor, hypertonia, myoclonus or seizures) in the newborn. This syndrome is usually delayed several hours to several days after birth. Cases of respiratory problems in newborns have also been reported. Therefore, if the mother is treated until the end of the pregnancy, monitoring should be considered at birth and for several days afterwards.

Feeding with milk

Very small amounts of buprenorphine and its metabolites pass into breast milk. These quantities are not sufficient to avoid withdrawal syndrome which may be delayed in breastfed infants. After an assessment of individual risk factors, breastfeeding may be considered in patients treated with buprenorphine.

Fertility

In a study conducted with pharmacological doses in mice, testicular atrophy with tubular calcification was demonstrated in treated animals.

No adverse effects on fertility were observed in rat studies; however, birthing difficulties have been noted.

Effects on the ability to drive and use machines

Buprenorphine has a moderate influence on its ability to drive and use machines when administered to patients dependent on opioids. This medication can induce drowsiness, fatigue or mental confusion, especially during treatment induction and dose adjustment. If the product is the same as alcohol or depresses the central nervous system, the effect may be increased. Patients should be advised that the buprenorphine volume may affect their capacity to drive and use peligrosa machinery.

Side effects

Security Profile Summary

The most commonly reported adverse reactions in the pivotal clinical study were withdrawal syndrome-related effects (e.g. insomnia, headache, nausea and hyperhidrosis).

Tabulated list of adverse reactions

Table 1 presents the most frequently reported adverse reactions during a pivotal clinical study in patients treated with buprenorphine (n=103) versus placebo (n=107). The frequency of possible adverse reactions listed below is defined according to the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1,000); very rare (< 1/10,000).

Table 1 also summarizes the most frequently reported adverse reactions in the registrant's global pharmacovigilance database, identified in clinical studies and post-marketing product surveillance. The frequency is said to be indeterminate when the adverse effect was not identified in the pivotal clinical study.

Table 1: Adverse reactions observed in a pivotal clinical study and/or reported during pharmacovigilance, presented by system organ class

Organ system class	Very common	Frequent	Infrequent	Rare	Very rare	Undetermined frequency
Infections and infestations	Infection	Pharyngitis
Psychiatric disorders	Insomnia	Hustle Anxiety Nervousness		Hallucination
Nervous system disorders	Headache	Migraine Paresthesia Drowsiness Syncope Vertigo Hyperkinesis
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and medial conditions		Dyspnee		Respiratory depression(1)
Gastro-intestinal conditions	Nausees Abdominal pain	Constipation Vomissement
Skin and subcutaneous tissue disorders	Hyperhidrosis
Musculoskeletal and systemic conditions		Muscle spasms
Reproductive system and breast disorders		Dysmenorrhea Leukorrhea
General disorders and administration site conditions	Withdrawal syndrome	Asthenia				Neonatal withdrawal syndrome(2)
Immune system disorders						Hypersensitivity reactions (3)
Liver disorders						Increased transaminases, hepatitis, jaundice(4)

 

Description of certain side effects:

A summary of adverse reactions reported post-marketing that are considered serious or of interest is presented below:

1. Cases of respiratory depression have been observed. Deaths due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines or was not used according to the prescribing information. Deaths have also been reported during concurrent administration of buprenorphine and other CNS depressants such as alcohol or other opioids.


2. Neonatal withdrawal syndrome has been reported in newborns of women who received buprenorphine during pregnancy. The syndrome may be milder and longer than that induced by short-acting full µ-opioid receptor agonists. The nature of the syndrome may vary depending on the mother's history of drug use.


3. The most common signs and symptoms of hypersensitivity include rash, hives and pruritus. Bronchospasm, respiratory depression, angioedema and anaphylactic shock have been reported.


4. Cases of elevated liver transaminases and hepatitis with jaundice generally with a favorable outcome have been observed.

Overdose

The partial opioid agonist properties of buprenorphine give it a high therapeutic index.

Symptoms

The main symptom requiring medical intervention in the event of an overdose is respiratory depression secondary to central nervous system depression, as it can lead to respiratory arrest and death. Other signs of overdose include sedation, miosis, hypotension, nausea and vomiting.

Treatment / Support

In the event of an overdose, comprehensive management must be instituted, including close monitoring of the patient's respiratory and cardiac condition.

• Symptomatic treatment of respiratory depression and standard intensive care measures should be implemented. Clearance of the upper airway as well as assisted or controlled ventilation should be ensured if necessary. The patient must be transferred to a unit with all the necessary resuscitation resources.


• If the patient vomits, precautions should be taken to prevent them from inhaling their vomit.


• The use of an injectable opioid antagonist (i.e. naloxone) is recommended, despite the modest effect it may have in suppressing respiratory symptoms induced by the use of buprenorphine, the latter being strongly linked to opioid receptors.


• When using naloxone, the long duration of action of buprenorphine should be taken into account to determine the duration of treatment and medical supervision necessary to suppress the effects of overdose. Naloxone may be eliminated more quickly than buprenorphine; therefore, symptoms of buprenorphine overdose previously controlled by naloxone may recur. Continuous infusion may be necessary. Continuous IV infusion rates should be titrated to patient response. If this is not possible, a repeat dose of naloxone may be required.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

• Pharmacotherapeutic group: drug used in opioid dependence, ATC code: N07BC01.


• Buprenorphine is an opioid agonist-antagonist and binds to brain m and k receptors. Its activity in opioid substitution treatment is attributed to its slowly reversible binding to m-receptors which would minimize the need for narcotic addicts over a long period of time.


• The partial agonist activity of buprenorphine gives the product a high therapeutic index by limiting its depressant effects, particularly on cardio-respiratory functions. The therapeutic margin of buprenorphine may be reduced when combined with benzodiazepines or in situations of misuse of buprenorphine.

Pharmacokinetic properties

Absorption

• Orally, buprenorphine undergoes N-dealkylation and glucuronidation in the small intestine and liver by a significant first-pass effect. Oral administration of the drug is therefore inappropriate.


• Sublingually, the absolute bioavailability of buprenorphine is poorly known, but has been estimated between 15 and 30%. Peak plasma concentration is obtained 90 minutes after sublingual administration, and the maximum dose-concentration relationship is linear between 2 and 16 mg.

Distribution

Absorption of buprenorphine is followed by a rapid distribution phase. The half-life is 2 to 5 hours.

Metabolism and elimination

• Buprenorphine is metabolized by 14-N-dealkylation, and glucuronidation of the parent molecule and the dealkylated metabolite. Clinical data support that CYP3A4 is responsible for the N-dealkylation of buprenorphine.


• N-desalkylbuprenorphine is an m-agonist with low intrinsic activity.


• The elimination of buprenorphine is bi- or tri-exponential, with a long terminal elimination phase of 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature. of the molecule.


• Buprenorphine is mainly eliminated in the feces by biliary excretion of glucuronide metabolites (70%), with the remainder being eliminated in the urine.

Special populations

Hepatic insufficiency

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone was evaluated in a single-dose post-marketing study.

Table under summarizes the results of a clinical study in which exposure after administration of buprenorphine/naloxone 2 mg/0.5 mg sublingual tablet was determined in healthy subjects, and in subjects with varying degrees of hepatic impairment. .

Effect of hepatic impairment on the pharmacokinetic parameters of buprenorphine after administration of buprenorphine/naloxone (change compared to healthy subjects)
PK settings	Mild Hepatic Failure (Child-Pugh Class A) (n=9)	Moderate Hepatic Failure (Child-Pugh Class B) (n=8)	Severe Liver Failure (Class C Child-Pugh) (n=8)
Buprenorphine
Cmax	1.2 times more	1.1 times more	1.7 times more

Plasma exposure to buprenorphine was approximately 3 times higher in patients with severe hepatic impairment after administration of a single dose of 2 mg.

Preclinical safety data

• Chronic toxicity studied in four animal species (rodents and non-rodents) with four different routes of administration did not show any clinically relevant element. In a one-year oral study in dogs, hepatic toxicity was observed at very high doses (75 mg/kg).


• Teratogenesis studies carried out in rats and rabbits allow us to conclude that buprenorphine is neither embryotoxic nor fetotoxic.


• No side effects on fertility were reported in rats, however, high peri- and post-natal mortality was observed in this species after oral and IM administration, linked to difficulty in giving birth and insufficient lactation.


• No evidence of genotoxic potential was found in a standard battery of tests.


• Carcinogenesis studies in mice and rats do not show a difference in the incidence of different types of tumors between animals treated with buprenorphine and the control group. However, in a study conducted with pharmacological doses in mice, testicular atrophy with tubular calcification was demonstrated in treated animals.