Buprenorphine 2 Mg Sublingual Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Buprenorphine 2 mg sublingual tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Buprenorphine 2mg: each tablet contains 2.16mg buprenorphine hydrochloride equivalent to 2mg buprenorphine.
Excipients with known effect:
Each tablet contains 29.85mg of anhydrous lactose and 0.25mg of butylated hydroxyanisole (E320).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Sublingual tablet
2 mg tablet: White to off-white, round, biconvex uncoated sublingual tablet debossed with “2” on one side and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Buprenorphine is indicated as a substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment.
Treatment is intended for use in adults and adolescents aged 16 years or older who have agreed to be treated for addiction.
4.2 Posology and method of administration
Posology Induction therapy
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
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.
The initial dose is from 0.8mg to 4mg, administered as a single daily dose. 0.4mg dose strength of Buprenorphine is not available. If low dose is required, the patient should use tablets (0.4mg) of another brand.
- For opioid-dependent drug addicts who have not undergone withdrawal: one dose of buprenorphine tablet(s) administered sublingually at least 4-6 hours after the last use of the opioid, or when the first signs of craving withdrawal 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 dosage should be individualised for each patient. The maintenance dosage will vary between individuals and should be determined by progressively increasing the dose until the minimal effective dose is identified. The mean maintenance daily dose is 8mg. The majority of patients will not require doses exceeding 16mg/day, however, the efficacy and safety of buprenorphine tablets was tested in clinical trials in doses up to 24mg per day.
The dosage is titrated according to reassessment of the clinical status and global management of the patient. Unsatisfactory stabilisation on 16mg per day may be related to potential misuse or psychiatric comorbidities. In these cases alternative treatment options should be taken into account.
Daily dispensing of buprenorphine is recommended, particularly during the initiation of treatment. Then, after stabilisation, the patient may be given a supply of the product sufficient for several days of treatment. However, it is recommended that the amount of the product dispensed be 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 0.4mg, 2mg and 8mg, 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 hepatic impairment
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 renal impairment
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).
Paediatric population
There are no clinical data on efficacy and safety for the use of Buprenorphine in children and adolescents. Therefore, Buprenorphine should not be used in children and adolescents under the age of 16.
Method of administration
Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this medicinal product. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.
The result of the treatment depends on the dosage prescribed as well as on the combined medical, psychological, social and educational measures taken in monitoring the patient.
4.3
Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Severe respiratory insufficiency
- Severe hepatic insufficiency
- Acute alcoholism or delirium tremens
4.4 Special warnings and precautions for use
Due to lack of data in adolescents (age 16-18), buprenorphine should be used only with caution in this age group.
Warnings
Buprenorphine sublingual tablets are indicated 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).
- 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. Buprenorphine binds to the p and k opiate receptors.
- Due to misuse risk, especially by intravenous route, and posology adaptation, prescription duration should be brief particularly at the beginning of the treatment. If possible, a controlled or partial dispensing should be implemented in order to favour also treatment compliance. Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.
- 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.
- 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 and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing 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. Serious cases of acute hepatic injury have also been reported in a context of misuse, especially by intravenous route. These hepatic injuries have mainly been observed at the high doses and could be due to a mitochondrial toxicity (genetic diseases, viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiretroviral nucleoside analogues, and the concurrent use of other potentially hepatotoxic medicinal products).
- Because CYP3A4 inhibitors (see section 4.5) may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine titrated carefully since a reduced dosing may be sufficient in these patients.
- Buprenorphine can precipitate withdrawal symptoms in opioid-dependent patients particularly if administered less than 4-6 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.
- 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.
- Studies in animals, as well as clinical experience, have shown that buprenorphine may produce dependence but at a lower level than morphine. Consequently, it is important to follow the recommendations for initiating treatment, dosage adjustment and monitoring of the patient (see section 4.2).
- Athletes should be aware that this medicinal product may cause a positive reaction to “anti-doping tests.”
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.
As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.
Excipients
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains butylated hydroxyanisole (E320), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
4.5 Interaction with other medicinal products and other forms of interaction
Buprenorphine should not be taken together with alcoholic drinks or medicinal products 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 (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. Buprenorphine should not be administered concomitantly or until two weeks after the end of treatment with MAOI.
- Naltrexone: risk of withdrawal syndrome.
- 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.
Further titration of buprenorphine should be made as clinically indicated. 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 medicinal products 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.
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of buprenorphine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
At the end of pregnancy, high doses, even for a short duration of time, may induce respiratory depression in new-born infants. During the last three months of pregnancy, chronic use of buprenorphine may be responsible for a withdrawal syndrome in new-born infants. Buprenorphine should only be used during pregnancy in case the potential benefits outweigh the risks.
Breast-feeding
Buprenorphine is excreted in human breast milk. In rats, buprenorphine has the potential to inhibit lactation or milk production. Therefore buprenorphine should not be used during breast-feeding.
Fertility
There are no fertility data at all for the use of buprenorphine.
4.7 Effects on ability to drive and use machines
Buprenorphine has minor to moderate influence on the ability to drive and use machine. 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).
4.8
Undesirable effects
The onset of undesirable effects depends on the patient's tolerance threshold, which is higher in drug addicts than in the general population.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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 from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1 presents undesirable effects reported in clinical trials.
|
Table 1: Frequency of Adverse Reactions | ||
|
System Organ Class |
Frequency |
Buprenorphine 2 mg sublingual tablets |
|
Psychiatric disorders |
Rare |
Hallucinations |
|
Nervous system disorders |
Common |
Insomnia, headache, fainting, drowsiness |
|
Vascular disorders |
Common |
Orthostatic hypotension |
|
Respiratory, thoracic and mediastinal disorders |
Rare |
Respiratory depression |
|
Gastrointestinal disorders |
Common |
Constipation, nausea and vomiting |
|
General disorders and administration site conditions |
Common |
Asthenia, sweating |
|
Immune system disorders |
Very rare |
Hypersensitivity reactions like rash, urticaria, pruritus, bronchospasms, angioneurotic oedema, anaphylactic shock. |
|
Hepatobiliary disorders |
Very rare |
After normal use: increase of transaminases and icteric hepatitis. After IV misuse: potentially serious acute hepatitis |
|
Skin and subcutaneous tissue disorders |
Very rare |
After IV misuse: local reactions, sometimes septic. |
In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
In the event of accidental 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: other nervous system drugs; drugs used in addictive disorders; 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.
Due to its partial opioid agonist activity, buprenorphine has a wide margin of safety, which limits its depressant effects, particularly on cardiac and respiratory functions. The margins of safety can be reduced if combined with benzodiazepines or if buprenorphine is misused.
5.2 Pharmacokinetic properties
Absorption
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. N-dealkylation and glucuroconjugation also take place in 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 and the maximal dose-concentration relationship is linear, between 2mg and 16mg.
Distribution
The absorption of buprenorphine is followed by a rapid distribution phase and a half-life of 2 to 5 hours.
Biotransformation
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
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
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.
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
citric acid anhydrous Sodium citrate dihydrate Povidone K30
Butylated hydroxyanisole (E320)
Maize starch
Maize starch pregelatinised Magnesium stearate.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister consists of PVC, PVDC, aluminium and heat seal lacquer lidding foil.
Pack size: 7 and 28 sublingual tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87 2132 JH Hoofddorp The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 31750/0043
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/03/2015
10 DATE OF REVISION OF THE TEXT
30/03/2015