Buprenorphine 0.4 Mg Sublingual Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Buprenorphine 0.4 mg sublingual tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sublingual tablet contains 0.4 mg of buprenorphine (as buprenorphine hydrochloride).
Excipient: each tablet contains 19,71mg lactose monohydrate.
Excipient(s) with known effects:
This medicinal product contains lactose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Sublingual tablet.
White, round, biconvex uncoated tablet with embossed on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment.
4.2 Posology and method of administration
Treatment intended for use in adults and adolescents aged over 15 years who have agreed to be treated for addiction.
When initiating buprenorphine treatment, the physician should be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients.
Prior to treatment induction, consideration should be given to the type of opioid dependence (i.e. long- or short- acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid precipitating withdrawal, induction with buprenorphine should be undertaken when objective and clear signs of withdrawal are evident.
Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this drug. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.
Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medication (see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4).
Induction therapy
The initial dose is from 0.8mg to 4mg, administered as a single daily dose.
• For opioid-dependent drug addicts who have not undergone withdrawal: one dose of buprenorphine tablet(s) administered sublingually at least 6 hours after the last use of the opioid, or when the first signs of craving appear.
• For patients receiving methadone: before beginning buprenorphine therapy, the dose of methadone should be reduced to a maximum of 30mg/day.
Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.
Dosage adjustment and maintenance:
The dose of buprenorphine should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient.
Distribution of buprenorphine on a daily basis is recommended in the first period of treatment. Later on, as soon as the patient is stabilized, a supply for several days of treatment could be given (limited to a maximum of 7 days or according to local requirements).
Dosage reduction and termination of treatment:
After a satisfactory period of stabilisation has been achieved, the dosage may be reduced gradually to a lower maintenance dose; when deemed appropriate, treatment
may be discontinued in some patients. The availability of the sublingual tablet in doses of 0.4 mg, 2 mg and 8 mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.
Patients with impaired hepatic function:
The effect of hepatic impairment on the pharmacokinetics of buprenorphine is unknown. Since buprenorphine is extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment.
Patients with impaired renal_function:
Modification of the buprenorphine dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (CLcr<30ml/min) (see section 5.2).
4.3 Contraindications
- Hypersensitivity to buprenorphine or any of the excipients
- Children and adolescents less than 15 years of age
- Severe respiratory insufficiency
- Severe hepatic insufficiency
- Acute alcoholism or delirium tremens
- Breast feeding
4.4 Special warnings and precautions for use
Due to the lack of data in adolescents (age 15-18), buprenorphine should be used only with caution in this age group.
Warnings
Buprenorphine is recommended only for the treatment of opioid drug dependence. It is also recommended that treatment is prescribed by a physician who ensures comprehensive management of the drug addicted patient(s).
- The clinician should consider the risk of abuse and misuse (e.g. IV administration), particularly at the beginning of the treatment.
- Diversion: diversion refers to the introduction of sublingual buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. This diversion may lead to new addicts using sublingual buprenorphine as the primary drug of abuse with the risk of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury.
- Precipitated Withdrawal: when initiating treatment with sublingual buprenorphine the physician must be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients particularly if administered less than 6 hours after the last use of heroin or other short-acting opioids, or if administered less than 24 hours after the last dose of methadone. Conversely, withdrawal symptoms may also be associated with suboptimal dosing.
The risk of serious adverse events such as overdose or treatment dropout is greater if a patient is under treated with sublingual buprenorphine and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines.
- Dependence: buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Discontinuation of treatment may result in a withdrawal that may be delayed.
- Respiratory Depression: some cases of death due to respiratory depression have been reported, particularly when used in combination with benzodiazepines (see section 4.5) or when buprenorphine was not used according to labelling.
- Hepatitis, hepatic events: cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure. In many cases the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant use of other potentially hepatotoxic drugs (aspirin, amiodarone, protease inhibitors, isoniazide..) and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing sublingual buprenorphine and during treatment. When a hepatic event is suspected and the causality is unknown, further evaluation is required. If buprenorphine is suspected to be the cause of hepatic necrosis or jaundice, it must be discontinued as rapidly as the patient’s clinical condition permits. All patients should have liver function tests performed at regular intervals.
- Dose adjustments should be performed with care in patients using CYP3A4 inhibitors, as CYP3A4 inhibitors may enhance buprenorphine plasma levels (see section 4.5). Patients using CYP3A4 inhibitors may be treated with lower doses.
- This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see section 4.5).
- This product can cause orthostatic hypotension.
- Athletes should be aware that this medicine may cause a positive reaction to “anti-doping tests.”
Paediatric Use
No data are available in children below 15 years of age; therefore, buprenorphine should not be used in children under the age of 15.
Precautions for use
This product should be used with care in patients with:
• asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine);
• renal insufficiency (20% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged);
• hepatic insufficiency (hepatic metabolism of buprenorphine may be altered);
• as with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.
Excipient:
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Buprenorphine should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine (see section 4.7).
Buprenorphine should be used cautiously together with:
• Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore, dosages must be individually titrated and the patient monitored carefully. The risk of drug abuse should also be considered (see section 4.4).
• Other central nervous system depressants; other opioid derivatives (e.g. methadone, analgesics and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. This combination increases central nervous system depression.
• Monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine.
• To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.
A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.
An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC of buprenorphine (approximately 70% and 50% respectively) and, to a lesser extent, of the metabolite, norbuprenorphine. Patients receiving buprenorphine should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole.
Although no data from clinical trials are available, the use of other inhibitors of CYP3A4 (e.g. gestodene, troleandoymycin, the HIV protease inhibitors ritonavir, indinavir and saquinavir) may also increase exposure levels to buprenorphine and norbuprenorphine and a similar dose-reduction should be considered when initiating treatment.
The interaction of buprenorphine with CYP 3A4 inducers has not been investigated, therefore it is recommended that patients receiving buprenorphine should be closely monitored if enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. Use of these medications may increase the metabolism of buprenorphine and the dose of buprenorphine should be increased appropriately if patients complain of decreased benefit from buprenorphine or if there is re-emergence of craving for illicit drugs.
4.6 Pregnancy and lactation
Pregnancy
In humans, there is currently not sufficient data to evaluate potential malformative or foetotoxic effects of buprenorphine when administered during pregnancy.
At the end of pregnancy, high doses, even for a short duration of time, may induce respiratory depression in neonates. During the last three months of pregnancy, chronic use of buprenorphine may be responsible for a withdrawal syndrome in neonates. Buprenorphine should not be used during pregnancy unless the clinical condition of the woman requires treatment with buprenorphine, and if the potential benefit justifies the potential risk to the fetus.
Breast-feeding
As evidenced in rats, buprenorphine has the potential to inhibit lactation or milk production. In addition, because buprenorphine passes into the mother's milk, breastfeeding is contra-indicated.
4.7 Effects on ability to drive and use machines
Buprenorphine may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants. Therefore, patients should be warned against driving or operating machinery (see section 4.5).
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive.
• Do not drive until you know how the medicine affects you.
• It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the ‘statutory defence’).
• This defence applies when:
o The medicine has been prescribed to treat a medical or dental problem; and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.
• Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law
4.8 Undesirable effects
The onset of side effects depends on the patient's tolerance threshold, which is higher in drug addicts than in the general population.
The following frequency convention is used in the evaluation of undesirable effects:
Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated form the available data).
|
Immune system disorder |
Very rare: |
Anaphylactic shock, angioneurotic oedema (Quincke-oedema), bronchospasm |
|
Psychiatric disorders |
Common: |
Anxiety, nervousness |
|
Uncommon: |
Hallucinations | |
|
Nervous system disorders |
Very Common: |
Insomnia |
|
Common |
Dizziness, drowsiness, headache | |
|
Eye disorders |
Common: |
Lacrimation disorder |
|
Cardiac disorders |
Common: |
ECG abnormalities (QT prolongation) |
|
Vascular disorders |
Common: |
Syncope, orthostatic hypotension |
|
Respiratory, thoracic and mediastinal disorders |
Common: |
Rhinorrhoea |
|
Uncommon: |
Respiratory depression | |
|
Gastrointestinal disorders |
Common: |
Constipation, diarrhoea, nausea, vomiting, abdominal pain |
|
Hepatobiliary disorders |
Uncommon: |
Hepatic necrosis, hepatitis |
|
Skin and subcutaneous tissue disorders |
Common: |
Sweating |
|
General disorders |
Very common: |
Asthenia, withdrawal syndrome |
|
Common: |
Back pain, chills |
In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V
4.9 Overdose
In the event of overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Treatment: Symptomatic treatment of respiratory depression, following standard intensive care measures, should be instituted. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment within which full resuscitation facilities are available. Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid agents.
The long duration of action of buprenorphine should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence. ATC code: N07 BC01
Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the p (mu) and k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the p receptors which, over a prolonged period, minimises the need of the addicted patient for drugs.
During clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, “good effect”, and respiratory depression.
5.2 Pharmacokinetic properties
Absorption
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. The use of this medication by the oral route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose-concentration relationship is linear, between 2 mg and 16 mg.
Distribution
The absorption of buprenorphine is followed by a rapid distribution phase and a halflife of 2 to 5 hours.
Biotransformation and elimination
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjugation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a p (mu) agonist with weak intrinsic activity.
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 essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (80%), the rest being eliminated in the urine.
5.3 Preclinical safety data
Acute toxicity of buprenorphine was determined in the mouse and rat following oral and parenteral administration. The median lethal doses (LD50) in the mouse were 26, 94 and 261 mg/kg for intravenous, intraperitoneal and oral administration, respectively. The LD50 values in the rat were 35, 243, and 600 mg/kg for intravenous, intraperitoneal and oral administration, respectively.
When beagles were dosed continuously subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months, buprenorphine showed remarkably low tissue and biochemical toxicities.
From teratology studies in rats and rabbits, it was concluded that buprenorphine is not embryotoxic or teratogenic, and it does not have any marked effects on weaning potential. There were no adverse effects on fertility or general reproductive function in rats, although at the highest intramuscular dose (5mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal mortality. Studies in rats and rabbits have evidenced foetotoxicity including post-implantation loss. In addition, maternal oral administration at high doses during gestation and lactation resulted in a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.
Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks of oral dosing of 75mg/kg/day.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate
Mannitol
Maize starch
Citric acid, anhydrous
Sodium citrate
Povidone K30
Sodium stearyl fumarate
6.2 Incompatibilities
Not applicable.
6.3. Shelf life
1 year
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package to protect from light and moisture.
6.5 Nature and contents of container
PVC/Aluminium Blister Packs.
Pack sizes 7, 28, 70 sublingual tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Ethypharm
194 Bureaux de la Colline 92213 Saint Cloud France
8 MARKETING AUTHORISATION NUMBER(S)
PL 06934/0102
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/09/2009
10 DATE OF REVISION OF THE TEXT
18/06/2015