Buprenorphine has a wide safety margin. Due to the rate-controlled delivery of small amounts of buprenorphine into the blood circulation high or toxic buprenorphine concentrations in the blood are unlikely. The maximum serum concentration of buprenorphine after the application of the Norspan 70 micrograms/h transdermal patch is about six times less than after the intravenous administration of the therapeutic dose of 0.3 mg buprenorphine.
Symptoms
In principal, on overdose with buprenorphine, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These are: respiratory depression, sedation, somnolence, nausea, vomiting, cardiovascular collapse, and marked miosis.
Treatment
General emergency measures apply. Keep the airway open (aspiration!), maintain respiration and circulation depending on the symptoms. Naloxone has a limited impact on the respiratory depressant effect of buprenorphine. High doses are needed given either as repeated boluses or infusion (for example starting with a bolus administration of 1-2 mg intravenously. Having attained an adequate antagonistic effect, administration by infusion is recommended to maintain constant naloxone plasma levels). Therefore, adequate ventilation should be established.
- opioid-dependent patients and for narcotic withdrawal treatment
- conditions in which the respiratory centre and function are severely impaired or may become so
- patients who are receiving MAO inhibitors or have taken them within the last two weeks
- patients suffering from myasthenia gravis
- patients suffering from delirium tremens.
- pregnancy
Not applicable.
The following adverse reactions were reported after administration of Norspan in clinical studies and from postmarketing surveillance.
The frequencies are given as follows:
Very common (>1/10)
Common (>1/100, <1/10)
Uncommon (>1/1,000, <1/100)
Rare (>1/10,000, <1/1,000)
Very rare (≤1/10,000)
Not known (cannot be estimated from the available data)
a) The most commonly reported systemic adverse reactions were nausea and vomiting.
The most commonly reported local adverse reactions were erythema and pruritus.
b)
| Immune system disorders | |
| Very rare: | serious allergic reactions* |
| Metabolism and nutrition disorders | |
Rare: | appetite lost |
| Psychiatric disorders | |
Uncommon: | confusion, sleep disorder, restlessness |
| Rare: | psychotomimetic effects (e.g. hallucinations, anxiety, nightmares), decreased libido |
| Very rare: | dependence, mood swings |
| Nervous system disorders | |
| Common: | dizziness, headache |
| Uncommon: | sedation, somnolence |
| Rare: | concentration impaired, speech disorder, numbness, dysequilibrium, paraesthesia (e.g. pricking or burning skin sensation) |
| Very rare: | muscle fasciculation, parageusia |
| Eye disorders | |
| Rare: | visual disturbance, blurring of vision, eyelid oedema |
| Very rare: | miosis |
| Ear and labyrinth disorders | |
| Very rare: | ear pain |
| Cardiac/Vascular disorders | |
| Uncommon: | circulatory disorders (such as hypotension or, rarely, even circulatory collapse) |
| Rare: | hot flushes |
| Respiratory, thoracic and mediastinal disorders | |
| Common: | dyspnoea |
| Rare: | respiratory depression |
| Very rare: | hyperventilation, hiccups |
| Gastrointestinal disorders | |
| Very common: | nausea |
| Common: | vomiting, constipation |
| Uncommon: | dry mouth |
| Rare: | pyrosis |
| Very rare: | retching |
| Skin and subcutaneous tissue disorders | |
| Very common: | erythema, pruritus |
| Common: | exanthema, diaphoresis |
| Uncommon: | rash |
| Rare: | urticaria |
| Very rare: | pustules, vesicles |
| Renal and urinary disorders | |
| Uncommon: | urinary retention, micturition disorders |
| Reproductive system and breast disorders | |
| Rare: | decreased erection |
| General disorders and administration site conditions | |
| Common: | oedema, tiredness |
| Uncommon: | weariness |
| Rare: | withdrawal symptoms*, administration site reactions |
| Very rare: | thoracic pain |
* see section c)
c) In some cases delayed allergic reactions occurred with marked signs of inflammation. In such cases treatment with Norspan should be terminated.
Buprenorphine has a low risk of dependence. After discontinuation of Norspan, withdrawal symptoms are unlikely. This is due to the very slow dissociation of buprenorphine from the opiate receptors and to the gradual decrease of buprenorphine serum concentrations (usually over a period of 30 hours after removal of the last transdermal patch). However, after long-term use of Norspan withdrawal symptoms, similar to those occurring during opiate withdrawal, cannot be entirely excluded. These symptoms include: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastro-intestinal disorders.
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
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Standard toxicological studies have not shown evidence of any particular potential risks for humans. In tests with repeated doses of buprenorphine in rats the increase in body weight was reduced.
Studies on fertility and general reproductive capacity of rats showed no detrimental effects. Studies in rats and rabbits revealed signs of fetotoxicity and increased postimplantation loss.
Studies in rats showed diminished intra-uterine growth, delays in the development of certain neurological functions and high peri/post natal mortality in the neonates after treatment of the dams during gestation or lactation. There is evidence that complicated delivery and reduced lactation contributed to these effects. There was no evidence of embryotoxicity including teratogenicity in rats or rabbits.
In vitro and in vivo examinations on the mutagenic potential of buprenorphine did not indicate any clinically relevant effects.
In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.
Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.
Pharmacotherapeutic group: Opioids, Oripavine derivatives. ATC code: N02AE01.
Buprenorphine is a strong opioid with agonistic activity at the mu-opioid receptor and antagonistic activity at the kappa-opioid receptor. Buprenorphine appears to have the general characteristics of morphine, but has its own specific pharmacology and clinical attributes.
In addition, numerous factors, e.g. indication and clinical setting, route of administration and the interindividual variability, have an impact on analgesia and therefore have to be considered when comparing analgesics.
In daily clinical practice different opioids are ranked by a relative potency, although this is to be considered a simplification.
The relative potency of buprenorphine in different application forms and in different clinical settings has been described in literature as follows:
- Morphine p.o. : BUP i.m. as 1 : 67 - 150 (single dose; acute pain model)
- Morphine p.o. : BUP s.l. as 1 : 60 - 100 (single dose, acute pain model; multiple dose , chronic pain, cancer pain)
- Morphine p.o. : BUP TTS as 1 : 75 - 115 (multiple dose, chronic pain)
Abbreviations:
p.o = oral; i.m. = intramuscular; s.l. = sublingual; TTS = transdermal; BUP = buprenorphine
Adverse reactions are similar to those of other strong opioid analgesics. Buprenorphine appears to have a lower dependence liability than morphine.
a) General characteristics of the active substance
Buprenorphine has a plasma protein binding of about 96%.
Buprenorphine is metabolised in the liver to N-dealkylbuprenorphine (norbuprenorphine) and to glucuronide conjugated metabolites. 2/3 of the active substance is eliminated unchanged in the faeces and 1/3 eliminated as conjugates of unchanged or dealkylated buprenorphine via the urinary system. There is evidence of enterohepatic recirculation.
Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen - presumably due to biliary excretion, as enterohepatic circulation has not fully developed.
b) Characteristics of Norspan in healthy volunteers
After the application of Norspan, buprenorphine is absorbed through the skin. The continuous delivery of buprenorphine into the systemic circulation is by controlled release from the adhesive polymer-based matrix system.
After the initial application of Norspan the plasma concentrations of buprenorphine gradually increase, and after 12-24 h the plasma concentrations reach the minimum effective concentration of 100 pg/ml. From the studies performed with the Norspan 35 micrograms/h in healthy volunteers, an average Cmax of 200 to 300 pg/ml and an average tmax of 60-80 h were determined. In one volunteer study, Norspan 35 micrograms/h and Norspan 70 micrograms/h were applied in a cross-over design. From this study, dose proportionality for the different strengths was demonstrated.
After removal of Norspan the plasma concentrations of buprenorphine steadily decrease and are eliminated with a half-life of approx. 30 hours (range 22 - 36). Due to the continuous absorption of buprenorphine from the depot in the skin elimination is slower than after intravenous administration.
Norspan must only be used with particular caution in acute alcohol intoxication, convulsive disorders, in patients with head injury, shock, a reduced level of consciousness of uncertain origin, increased intracranial pressure without the possibility of ventilation.
Buprenorphine occasionally causes respiratory depression. Therefore care should be taken when treating patients with impaired respiratory function or patients receiving medicinal products which can cause respiratory depression.
Buprenorphine has a substantially lower dependence liability than pure opioid agonists. In healthy volunteer and patient studies with Norspan, withdrawal reactions have not been observed. However, after long-term use of Norspan withdrawal symptoms, similar to those occurring during opiate withdrawal, cannot be entirely excluded. These symptoms are: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
In patients abusing opioids, substitution with buprenorphine may prevent withdrawal symptoms. This has resulted in some abuse of buprenorphine and caution should be exercised when prescribing it to patients suspected of having drug abuse problems.
Buprenorphine is metabolised in the liver. The intensity and duration of effect may be altered in patients with liver function disorders. Therefore such patients should be carefully monitored during Norspan treatment.
Athletes should be aware that this medicine may cause a positive reaction to sports doping control tests.
Paediatric population
As Norspan has not been studied in patients under 18 years of age, the use of the medicinal product in patients below this age is not recommended.
Patients with fever / external heat
Fever and the presence of heat may increase the permeability of the skin. Theoretically in such situations buprenorphine serum concentrations may be raised during Norspan treatment. Therefore on treatment with Norspan, attention should be paid to the increased possibility of opioid reactions in febrile patients or those with increased skin temperature due to other causes.
Norspan has major influence on the ability to drive and use machines.
Even when used according to instructions, Norspan may affect the patient's reactions to such an extent that road safety and the ability to operate machinery may be impaired.
This applies particularly at the beginning of treatment, at any change of dosage and when Norspan is used in conjunction with other centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics.
Patients who are affected (e.g. feeling dizzy or drowsy or experience blurred or double vision) should not drive or use machines while using Norspan and for at least 24 hours after the patch has been removed.
Patients stabilized on a specific dosage will not necessarily be restricted if the above mentioned symptoms are not present.
Additional information for UK only
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
Posology
Patients over 18 years of age
The Norspan dosage should be adapted to the condition of the individual patient (pain intensity, suffering, individual reaction).).
To allow for individual dose adaptation in an adequate time period sufficient supplementary immediate release analgesics should be made available during dose titration.
The necessary strength of Norspan must be adapted to the requirements of the individual patient and checked at regular intervals.
After application of the first Norspan transdermal patch the buprenorphine serum concentrations rise slowly both in patients who have been treated previously with analgesics and in those who have not. Therefore initially, there is unlikely to be a rapid onset of effect. Consequently, a first evaluation of the analgesic effect should only be made after 24 hours.
The previous analgesic medication (with the exception of transdermal opioids) should be given in the same dose during the first 12 hours after switching to Norspan and appropriate rescue medication on demand in the following 12 hours.
Dose titration and maintenance therapy
Norspan should be replaced after 96 hours (4 days) at the latest. For convenience of use, the transdermal patch can be changed twice a week at regular intervals, e.g. always on Monday morning and Thursday evening. The dose should be titrated individually until analgesic efficacy is attained. If analgesia is insufficient at the end of the initial application period, the dose may be increased, either by applying more than one transdermal patch of the same strength or by switching to the next transdermal patch strength. At the same time no more than two transdermal patches regardless of the strength should be applied.
Before application of the next Norspan strength the amount of total opioids administered in addition to the previous transdermal patch should be taken into consideration, i.e. the total amount of opioids required, and the dosage adjusted accordingly. Patients requiring a supplementary analgesic (e.g. for breakthrough pain) during maintenance therapy may take for example one to two 0.2 mg buprenorphine sublingual tablets every 24 hours in addition to the transdermal patch. If the regular addition of 0.4 - 0.6 mg sublingual buprenorphine is necessary, the next strength should be used.
Paediatric population
As Norspan has not been studied in patients under 18 years of age, the use of the medicinal product in patients below this age is not recommended.
Elderly patients
No dosage adjustment of Norspan is required for elderly patients.
Patients with renal insufficiency
Since the pharmacokinetics of buprenorphine is not altered during the course of renal failure, its use in patients with renal insufficiency, including dialysis patients, is possible.
Patients with hepatic insufficiency
Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with liver insufficiency should be carefully monitored during treatment with Norspan.
Method of application
Norspan should be applied to non-irritated, clean skin on a non-hairy flat surface, but not to any parts of the skin with large scars. Preferable sites on the upper body are: upper back or below the collar-bone on the chest. Any remaining hairs should be cut off with a pair of scissors (not shaved). If the site of application requires cleansing, this should be done with water. Soap or any other cleansing agents should not be used. Skin preparations that might affect adhesion of the transdermal patch to the area selected for application of Norspan should be avoided.
The skin must be completely dry before application. Norspan is to be applied immediately after removal from the sachet. Following removal of the release liner, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds. The transdermal patch will not be affected when bathing, showering or swimming. However, it should not be exposed to excessive heat (e.g. sauna, infrared-radiation).
Norspan should be worn continuously for up to 4 days. After removal of the previous transdermal patch a new Norspan transdermal patch should be applied to a different skin site. At least one week should elapse before a new transdermal patch is applied to the same area of skin.
Duration of administration
Norspan should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Norspan is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Discontinuation of Norspan
After removal of Norspan buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with Norspan is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of Norspan. For the time being only limited information is available on the starting dose of other opioids administered after discontinuation of Norspan.
Any unused product or waste material should be disposed of in accordance with local requirements.
