Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: RB Pharmaceuticals Ltd 103 – 105 Bath Road, Slough Berkshire SL1 3UH
SUBUTEX sublingual tablets are recommended only for the treatment of opioid drug dependence. It is also recommended that 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 refers to the induction of SUBUTEX into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. The diversion may lead to new addicts using SUBUTEX as the primary drug of abuse with the risk of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury.
When initiating treatment with buprenorphine the physicians 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 SUBUTEX and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines.
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 4.5 Interaction with other medicaments and other forms of interaction) 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 Subutex and during treatment. When a hepatic event is suspected and the causality is unknown, further evaluation is required. If SUBUTEX 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 preformed at regular intervals.
This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see 4.5 Interactions with other medicaments and other forms of interaction.)
This product can cause orthostatic hypotension.
Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce a low level of dependence.
Athletes should be aware that this medicine may cause a positive reaction to “anti-doping tests”.
No data are available in children less than 16 years of age; therefore, SUBUTEX should not be used in children under the age of 16.
This product should be used with care in patients with:
Patients with lactose intolerance: This product contains lactose (see section 6.1). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
SUBUTEX should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine (see 4.7 Effects on the ability to drive vehicles or operate machinery).
SUBUTEX should be used cautiously together with:
A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.
An interaction study of buprenorphine with ketoconazoles (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 Subutex should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazoles.
Further titration of Subutex should be made as clinically indicated. Although no data from clinical trails are available, the use of other inhibitors of CYP3A4 (e.g. gestodene, troleandomycin, 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 CYP3A4 inducers has not been investigated, therefore it is recommended that patients receiving Subutex should be closely monitored if enzyme inducers (e.g. Phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. Use of these medications may increase 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.
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.
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. Consequently, the use of buprenorphine is not recommended during pregnancy.
As evidenced in rats, buprenorphine has the potential to inhibit lactation or milk production. In addition, because buprenorphine passes into the mother’s milk, breast-feeding is contra-indicated.
SUBUTEX may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants. Therefore, patients should be warned against driving or operation machinery (see 4.5 Interaction with other medicaments and other forms of interaction).
The onset of side effects depends on the patient’s tolerance threshold. Which is higher in drug addicts than in general population.
The symptoms most frequently observed with buprenorphine administration are:
Other side effects that have been reported are:
Cases of bronchospasm, angioneurotic oedema and anaphylactic shock has also been reported.
In case of IV misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see “Special warnings and special precautions for use”).
In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with Naloxone.
None known.
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