United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)
3. Remove the wafer carefully from the foil and take
out from the packaging immediately.
4. Place the wafer on the tongue and close your
mouth. Allow it to remain there for a few seconds
until it has dissolved. Try to avoid swallowing during
the first 2 minutes.
Do not eat or drink for at least 5 minutes.
If you take more Espranor than you should
Tell your doctor immediately or contact your nearest
hospital casualty department. Remember to take the
pack and any remaining wafers with you.
If you forget to take Espranor
You should tell your doctor and follow their
instructions. Do not take a double dose to make up for
the missed dose, unless your doctor tells you to.
If you stop taking Espranor
Do not suddenly stop taking the wafers unless told
to do so by your doctor, as this may cause withdrawal
If you have any further questions on the use of this
product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side
effects, although not everyone gets them.
For the first 24 hours of treatment, you may feel
uncomfortable with some mild opiate withdrawal
Tell your doctor immediately or seek urgent
medical attention if you experience uncommon side
effects, such as:
swelling of the face, lips, tongue or throat which
may cause difficulty in swallowing or breathing,
severe hives/nettle rash. These may be signs of a
life-threatening allergic reaction.
feeling sleepy and uncoordinated, have blurred
vision, have slurred speech, cannot think well or
clearly, or your breathing gets much slower than is
normal for you.
Also tell your doctor immediately if you experience
uncommon side effects such as:
severe tiredness, itching with yellowing of skin or
eyes. These may be symptoms of liver damage.
seeing of hearing things that are not there
Very common side effects (may effect more than 1 in
10 people) include:
Insomnia (inability to sleep), constipation, feeling
or being sick (nausea), sweating, headache, drug
Common side effects (may effect up to 1 in 10
Weight loss, swelling (hands and feet), tiredness,
drowsiness, anxiety, nervousness, tingling,
depression, decreased sexual drive, increase in
muscle tension, abnormal thinking, increased
tearing (watering eyes) or other tearing disorder,
blurred vision, flushing, increased blood pressure,
palpitations, widening of blood vessel, migraines,
runny nose, sore throat and painful swallowing,
increased cough, upset stomach or other stomach
discomfort, diarrhoea, abnormal liver function,
flatulence, vomiting, numbness of the tongue or
mouth, rash, itching, hives, pain, joint pain, muscle
pain, leg cramps (muscle spasm), difficulty in
getting or keeping an erection, urine abnormality,
abdominal pain, back pain, weakness, infection,
chills, chest pain, fever, flu-like symptoms, feeling of
general discomfort, accidental injury caused by loss
of alertness or co-ordination, faintness and dizziness,
drop in blood pressure on changing position from
sitting or lying down to standing.
Uncommon side effects (may effect up to 1 in 100
Swollen glands, agitation, tremor, abnormal
dream, excessive muscle activity. Not feeling like
yourself , medicine dependence, amnesia (memory
disturbance), loss of interest, exaggerated feeling of
well-being, convulsion (fits), speech disorder, small
pupil size, difficulty urinating, eye inflammation
or infection, rapid or slow heart beat, low blood
pressure, myocardial infarction (heart attack), chest
tightness, Shortness of breath, asthma, yawning,
pain and sores in mouth, tongue discolouration,
acne, skin nodule, hair loss, dry or scaling skin,
inflammation of joints, urinary tract infection,
abnormal blood tests, loss of appetite, blood in
urine, abnormal ejaculation, menstrual or vaginal
problems, kidney stone, sensitivity to heat or cold,
heat stroke, feelings of hostility.
Rare side effects (may effect up to 1 in 1000 people)
What is in this leaflet:
1. What Espranor is and what it is used for
2. What you need to know before you take Espranor
3. How to take Espranor
4. Possible side effects
5. How to store Espranor
6. Contents of the pack and other information
1. What Espranor Oral Lyophilisate is
and what it is used for
Espranor oral lyophilisate is a freeze-dried wafer
which dissolves rapidly on the tongue.
Espranor is used in adults and adolescent over
15 years of age, as part of a medical, social and
psychological treatment programme for addiction.
Espranor contains buprenorphine, an opioid
(narcotic) analgesic. When it is used for the treatment
of patients addicted to opiate (narcotic) drugs, such
as morphine or heroin, it acts as a substitute for these
drugs and therefore aids the patient in withdrawing
from them over a period of time.
If treatment is stopped abruptly, withdrawal
symptoms can occur.
2. What you need to know before you
Do not take Espranor if:
You have severe breathing problems
You have severe liver problems
You are alcohol dependent or suffer from acute
alcoholism including ‘the shakes’ or hallucinations
You are pregnant (unless your doctor tells you to
You are allergic (hypersensitive) to buprenorphine
or any of the other ingredients in Espranor (see
Warnings and Precautions
Talk to your doctor, pharmacist or nurse before
If you suffer breathing problems e.g. asthma
If you have kidney problems
If you have liver problems
If you are breastfeeding a baby
If any of the above applies to you, please tell your
doctor before taking Espranor as your doctor may
need to reduce your dose of Espranor or you may
need additional treatment to control it.
Espranor should not be given to children or
adolescents under 15 years old.
Other medicines and Espranor
Tell your doctor or pharmacist if you are taking, have
recently taken or might take any other medicines.
The following medicines have sedative effects (make
you feel sleepy/drowsy). These effects are increased
if these medicines are taken while you are being
treated with Espranor:
Benzodiazepines (medicines used to treat anxiety
or sleep disorders) e.g. diazepam (valium). Your
doctor will prescribe the correct dose for you.
Taking the wrong dose of benzodiazepines may
cause death due to respiratory failure (inability to
Barbiturates e.g. phenobarbital
Other opioids or opioid derivatives e.g. morphine,
strong pain killers or cough medicines
Certain antidepressants e.g. fluoxetine (Prozac)
Monoamine oxidase inhibitors (MAOI) (medicines
used to treat severe depression) e.g. phenelzine
Medicines that cause drowsiness such as
antihistamines or sedatives
Certain drugs used to treat high blood pressure
Antipsychotic drugs (medicines used to treat
certain mental disorders)
If you are taking any of the following medicines,
your doctor may need to prescribe a lower dose of
Ketoconazole (medicine used to treat a fungal
infection which can increase the levels of Espranor
in your blood if both are taken at the same time)
Gestodene (found in some contraceptive pills)
Drugs used to treat HIV e.g. ritonavir, indinavir and
Phenprocoumon (a blood thinning medicine)
If you are taking any of the following medicines,
your doctor may need to prescribe a higher dose of
Enzyme inducers e.g. phenobarbital,
carbamazepine, phenytoin and rifampicin
Naltrexone may prevent the therapeutic effects of
Espranor. If currently taking this medicine followed
by concomitant use of naltrexone, you may
experience a sudden onset of prolonged and intense
Please tell your doctor or pharmacist if you are taking
or have recently taken any other medicines, including
medicines obtained without a prescription.
Espranor with food, drink and alcohol
Espranor should not be taken at the same time as
food or drink.
You should not drink alcohol or take any medicines
that contain alcohol while taking Espranor as this will
increase the risk of drowsiness, respiratory depression
and fatal overdose.
Pregnancy, breast-feeding and fertility
Before taking Espranor, tell your doctor if you are
pregnant or trying to become pregnant. If you
become pregnant during treatment with Espranor,
tell your doctor straight away.
Since Espranor is passed into breast milk, you should
not breast feed while taking this medicine.
Ask your doctor or pharmacist for advice before
taking any medicine.
Driving and using machines
This medicine can cause drowsiness, which may
be made worse if you also drink alcohol or take
tranquilizers or anti-anxiety drugs. If you are drowsy,
do not drive or operate machinery.
This medicine can affect your ability to drive.
Do not drive whilst taking this medicine until you
know how this medicine affects you.
It may be an offence to drive if your ability to drive
safely is affected.
There is further information for patients who are
intending to drive in Great Britain – go to https://
Talk to your doctor or pharmacist if you are not sure
whether it is safe for you to drive while taking this
Important information about some of the
ingredients of Espranor
Espranor contains aspartame. Aspartame contains
a source of phenylalanine. This may be harmful for
people with phenylketonuria.
3. How to take Espranor
Always take Espranor exactly as your doctor or
pharmacist has told you. You should check with your
doctor or pharmacist if you are not sure.
When to start taking Espranor
Starting Espranor treatment if you are dependent
on heroin or a short acting opioid – your first dose of
Espranor should be taken at least 6 hours after you
last used the opioid or when signs of withdrawal
Starting Espranor treatment if you are dependent on
methadone or a long acting opioid – you will not start
treatment with this medicine until your daily dose of
methadone is 30 mg a day or less. The first dose of
Espranor should be taken when signs of withdrawal
appear, but not less than 24 hours after you last used
For the first 24 hours of treatment, you may feel
uncomfortable with some mild opiate withdrawal
symptoms e.g. sweating, feeling sick (see section 4
Possible side effects).
How much to take
Your doctor will decide what dose you need to start
During treatment your doctor will adjust your dose
depending upon your response. The maximum dose
is 18 mg daily. After a period of successful treatment,
your doctor may gradually reduce your dose and
depending on your condition, may stop it altogether.
Do not suddenly stop taking Espranor as this may
lead to withdrawal symptoms.
Instructions for use
Espranor is sensitive to moisture. Make sure your
hands are dry before handling the wafer. Take the
wafer by following the instructions below:
1. Tear a square off the blister pack along the
2. The foil is easily peelable. Do not force the wafer
through the foil as it is fragile and can easily break.
Instead, fold back the foil and then peel it off.
Slow or difficult breathing, liver injury with or
without jaundice, swelling of face and throat or life
threatening allergic reactions.
Side effects with unknown frequency (frequency
cannot be estimated from the available data) include:
Sudden withdrawal syndrome caused by taking
Espranor too soon after use of illicit opioids, drug
withdrawal syndrome in newborn.
If any of the side effects get serious, or if you notice
any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
If you are not sure what the side effects listed are, ask
your doctor to explain them to you.
Reporting of side effects
If you get any side effects, talk to your doctor or
pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. You can also report
side effects directly via the Yellow Card Scheme
By reporting the side effects you can help provide
more information on the safety of this medicine.
5. How to store Espranor
Keep this medicine out of the sight and reach of
Do not use Espranor after the expiry date, which is
stated on the carton after EXP. The expiry date refers
to the last day of that month.
Store your medicine in the original packaging to
protect from light and moisture.
Espranor does not require any special temperature
Do not throw away any medicines via wastewater or
household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures
will help to protect the environment.
6. Contents of the pack and other
What Espranor contains:
The active substance is buprenorphine (as
buprenorphine hydrochloride). Each oral
lyophilisate (wafer) contains 2 mg or 8 mg of
The other ingredients are gelatin, mannitol,
aspartame, mint flavour and citric acid.
What Espranor looks like and the contents of the
Espranor 2 mg oral lyophilisate is a white to off-white
circular oral lyophilisate (wafer) marked with “M2” on
Espranor 8 mg oral lyophilisate is a white to off-white
circular oral lyophilisate (wafer) marked with “M8” on
Your medicine is available in blisters containing 7 or
28 wafers in an outer carton.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Martindale Pharmaceuticals Ltd
Manufacturer - Batch Release Site:
Macarthys Laboratories Limited
T/A Martindale Pharma
Essex, RM3 8UG
This medicinal product is authorised in the Member
states of the EEA under the following names:
Espranor 2 mg oral lyophilisate
Espranor 8 mg oral lyophilisate
Espranor 2 mg frystorkad tablett
Espranor 8 mg frystorkad tablett
Espranor 2 mg oral lyophilisate
Espranor 8 mg oral lyophilisate
This leaflet was last updated in March 2017
Espranor 2 mg Oral Lyophilisate: PL 00156/0364
Espranor 8 mg Oral Lyophilisate: PL 00156/0365
Read all of this leaflet carefully before you
start taking this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your
doctor, pharmacist or nurse.
This medicine has been prescribed for you only.
Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor,
pharmacist or nurse. This includes any possible
side effects not listed in this leaflet. See Section 4.
PACKAGE LEAFLET: INFORMATION FOR THE USER
Espranor 2 mg Oral Lyophilisate
Espranor 8 mg Oral Lyophilisate
100mm Measurement Verification Bar
Espranor is not interchangeable with other oral
buprenorphine products and the dose of Espranor
may differ from the dose of other buprenorphine
Take Espranor by placing ON your tongue, not
under your tongue.
Espranor 2 mg oral lyophilisate.
Summary of Product Characteristics Updated 21-Nov-2017 | Martindale Pharma
1. Name of the medicinal product
Espranor 2 mg oral lyophilisate.
2. Qualitative and quantitative composition
Each oral lyophilisate contains 2 mg of buprenorphine (as hydrochloride).
Each oral lyophilisate contains 0.50 mg aspartame.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
White to off-white circular oral lyophilisate with a diameter of 10.3 mm, debossed with 'M2' on one side.
4. Clinical particulars
4.1 Therapeutic indications
Substitution treatment for opioid drug dependence, within a framework of medical, social and
Treatment with Espranor oral lyophilisate is intended for use in adults and adolescents aged 15 years or
over who have agreed to be treated for addiction.
4.2 Posology and method of administration
Treatment should be under the supervision of a clinician experienced in the management of opiate
Espranor is not interchangeable with other buprenorphine products. Different buprenorphine products
have different bioavailability. Therefore, the dose in mg can differ between products. Once the appropriate
dose has been identified for a patient with a certain product (brand), the product cannot readily be
exchanged with another product.
The route of administration for Espranor is on the tongue, not under it.
Administration is oromucosal. The oral lyophilisate should be taken from the blister unit with dry fingers,
and placed whole on the tongue until dispersed, which usually occurs within 15 seconds, and then
absorbed through the oromucosa. Swallowing should be avoided for 2 minutes. The oral lyophilisate
should be taken immediately after opening the blister. Patients should not consume food or drink for 5
minutes after administration.
Physicians must advise patients that the oromucosal route of administration is the only effective and safe
route of administration for this medicinal product. If the oral lyophilisate, or saliva containing
buprenorphine are swallowed, the buprenorphine will be metabolised and excreted and have minimal
Adults and adolescents aged 15 years or over
Precautions to be taken before induction:
Prior to treatment initiation, 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 (demonstrated e.g. by a score indicating mild to moderate withdrawal on
the validated Clinical Opioid Withdrawal Scale, COWS).
Opioid-dependent drug addicts who have not undergone withdrawal: When treatment starts, the first dose
of Espranor should be taken when signs of withdrawal appear, but not less than 6 hours after the patient
last used opioids (e.g. heroin; short acting opioids).
Patients receiving methadone: Before beginning Espranor therapy, the dose of methadone must be
reduced to a maximum of 30 mg/day. The long half-life of methadone should be considered when starting
buprenorphine therapy. The first dose of Espranor should be taken when signs of withdrawal appear, but
not less than 24 hours after the patient last used methadone. Buprenorphine may precipitate symptoms of
withdrawal in patients dependent upon methadone.
Because of the partial agonist profile of buprenorphine, the patient should be warned that the first 24
hours of buprenorphine substitution therapy may feel uncomfortable with some mild opiate withdrawal
Initiation therapy (induction):
The recommended starting dose is 2 mg of Espranor (1 Espranor 2 mg oral lyophilisate). An additional
one to two Espranor 2 mg oral lyophilisates may be administered on day one depending on the individual
During the initiation of treatment, daily supervision of dosing is recommended to ensure proper
placement of the dose on the tongue and to observe patient response to treatment as a guide to effective
dose titration according to clinical effect.
Dosage adjustment and maintenance: The dose of Espranor should then be adjusted according to clinical
effect with the aim of quickly stabilising the patient. The dosage can be titrated up or down according to
assessment of the clinical and psychological status of the patient in steps of 2-6 mg until the minimum
effective maintenance dose is achieved, but should not exceed a maximum single daily dose of 18 mg.
During the initiation of treatment, daily dispensing of buprenorphine is recommended. After stabilisation,
a reliable patient may be given a supply of Espranor sufficient for several days of treatment. It is
recommended that the amount of Espranor be limited to 7 days or according to local requirements.
Less than daily dosing: After satisfactory stabilisation has been achieved the frequency of Espranor
dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For
example, a patient stabilised to receive a daily dose of 8 mg may be given 16 mg on alternate days, with
no dose on the intervening days. In some patients, after a satisfactory stabilisation has been achieved, the
frequency of Espranor dosing may be decreased to 3 times a week (for example on Monday, Wednesday
and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose,
and the dose on Friday should be three times the individually titrated daily dose, with no dose on the
intervening days. However, the dose given on any one day should not exceed 18 mg. Patients requiring a
titrated daily dose > 8 mg/day may not find this regimen adequate.
Dosage reduction and termination of treatment: After a satisfactory stabilisation has been achieved, if the
patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some favourable
cases, treatment may be discontinued. The availability of Espranor in doses of 2 mg and 8 mg allows for a
downward titration of dosage. For patients who may require a lower buprenorphine dose, buprenorphine 1
mg or 0.4 mg sublingual tablets may be used. Patients should be monitored following termination of
treatment because of the potential for relapse.
The safety and efficacy of buprenorphine in the elderly over 65 years of age have not been established.
No recommendation on posology can be made.
The safety and efficacy of buprenorphine in children below the age of 15 years have not been established.
No data are available.
Patients with impaired hepatic function
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).
The effect of hepatic impairment on the pharmacokinetics of buprenorphine is unknown. Since
buprenorphine is extensively metabolised in the liver, the plasma levels will be expected to be higher in
patients with moderate or severe hepatic impairment.
As Espranor pharmacokinetics may be altered in patients with hepatic impairment, lower initial doses and
careful dose titration in patients with mild to moderate hepatic impairment are recommended (see section
5.2). Buprenorphine is contraindicated in patients with severe hepatic insufficiency (see section 4.3).
Patients with impaired renal function
Modification of the Espranor dose is not generally required in patients with renal impairment. Caution is
recommended when dosing patients with severe renal impairment (Creatinine Clearance < 30 ml/min)
(see section 4.4 and 5.2).
Method of administration
Physicians must warn patients that the route of administration is the only effective and safe route for this
medicinal product (see section 4.4). The oral lyophilisate is to be placed on the tongue until completely
dissolved. Patients should not swallow or consume food or drink until the lyophilisate is completely
dissolved. For further information, see the national guidelines for buprenorphine treatment.
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Severe respiratory insufficiency
- Severe hepatic impairment
- Acute alcoholism or delirium tremens
4.4 Special warnings and precautions for use
Espranor oral lyophilisate is recommended only for the treatment of opioid drug dependence. It is also
recommended that the 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.
Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks
of misuse and abuse include overdose, spread of blood borne viral or localised and systemic infections,
respiratory depression and hepatic injury. Buprenorphine misused by someone other than the intended
patient poses the additional risk of new drug dependent individuals using buprenorphine as the primary
drug of abuse, and may occur if the medicine is distributed for illicit use directly by the intended patient
or if the medicine is not safeguarded against theft.
Sub-optimal treatment with buprenorphine may prompt medication misuse by the patient, leading to
overdose or treatment dropout. A patient who is under-dosed with buprenorphine may continue
responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other
sedative-hypnotics such as benzodiazepines.
To minimise the risk of misuse, abuse and diversion, physicians should take appropriate precautions when
prescribing and dispensing buprenorphine, such as to avoid take-home dosing early in treatment, and to
conduct patient follow-up visits with clinical monitoring that is appropriate to the patient's need.
Removal of Espranor from the mouth following supervised administration is virtually impossible due to
its rapid dispersal on the tongue.
When initiating treatment with 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. To avoid precipitating withdrawal, induction with
buprenorphine should be undertaken when objective signs of withdrawal are evident (see section 4.2).
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 Espranor and continues to self-medicate against withdrawal with opioids, alcohol or other
sedative-hypnotics, in particular benzodiazepines.
Respiratory Depression: A number of cases of death due to respiratory depression have been reported in
patients taking buprenorphine, particularly when used in combination with benzodiazepines (see section
4.5) or when buprenorphine was not used according to prescribing information. Deaths have also been
reported in association with concomitant administration of buprenorphine and other depressants such as
alcohol or other opioids. If buprenorphine is administered to some non-opioid dependent individuals, who
are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.
This product should be used with care in patients with asthma or respiratory insufficiency (e.g. chronic
obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-
existing respiratory depression or kyphoscoliosis (curvature of spine leading to potential shortness of
Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-dependent
persons in case of accidental or deliberate ingestion. Patients must be warned to store the blister safely, to
never open the blister in advance, to keep them out of the reach of children and other household members,
and not to take this medicine in front of children. An emergency unit should be contacted immediately in
case of accidental ingestion or suspicion of ingestion.
Hepatitis and 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 Espranor, and during treatment. When a hepatic event is suspected further biological
and etiological evaluation is required. Depending upon the findings, the medicinal product may be
discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use.
If the treatment is continued, hepatic function should be monitored closely.
Hepatic metabolism of buprenorphine may be altered in patients with hepatic impairment, which may
give rise to increased plasma concentrations of buprenorphine. A reduction of the buprenorphine dose
may be needed (see section 4.2).
Renal elimination may be prolonged since 30% of the administered dose is eliminated by the renal route.
Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended with
dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.2 and 5.2).
This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as
alcohol, tranquillisers, sedatives and hypnotics (see section 4.5).
Athletes should be aware that this medicine may cause a positive reaction to “anti-doping tests”.
This product contains aspartame (see Section 2 for the quantitative composition). Aspartame is a source
of phenylalanine which may be harmful for people with phenylketonuria.
Espranor is not recommended for use in children below age 15 years due to lack of data on safety and
Due to the lack of data in adolescents (aged 15- 18), Espranor should be used only with caution in this age
group and more closely monitored during treatment.
CYP 3A inhibitors
Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine.
A reduction of the buprenorphine dose may be needed. Patients already treated with CYP3A4 inhibitors
should have their dose of buprenorphine titrated carefully since a reduced dose may be sufficient in these
patients (see section 4.5).
Precautions for Use
This product can cause orthostatic hypotension.
Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be used
with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal
pressure may be increased or history of seizure.
As with other opioids, caution is advised when using buprenorphine in patients with head injury,
increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.
Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain as a
symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course of
Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal cortical
insufficiency (e.g., Addison's disease).
Opioids have been shown to increase intracholedochal pressure, and should be used with caution in
patients with dysfunction of the biliary tract.
Opioids should be administered with caution to elderly or debilitated patients.
The concomitant use of monoamine oxidase inhibitors (MAOI) might produce an exaggeration of the
effects of opioids, based on experience with morphine (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Espranor should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol
increases the sedative effect of buprenorphine (see section 4.7).
Espranor should be used cautiously when co-administered with:
- Benzodiazepines: This combination may result in death due to respiratory depression of central origin.
Therefore, dosages must be limited and this combination must be avoided in cases where there is a risk of
misuse. Patients should be warned that it is extremely dangerous to self-administer non-prescribed
benzodiazepines while taking this product, and should also be cautioned to use benzodiazepines
concurrently with this product only as directed by their physician (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. The reduced level of alertness can make driving and using machines
- Furthermore, adequate analgesia may be difficult to achieve when administering a full opioid agonist in
patients receiving buprenorphine. Therefore the potential to overdose with a full agonist exists, especially
when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels
- Naltrexone is an opioid antagonist that can block the pharmacological effects of buprenorphine. Co-
administration during buprenorphine treatment should be strongly avoided, due to the potentially
dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal
- CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor of
CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine (approximately
50 % and 70 % respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving Espranor
should be closely monitored, and may require dose-reduction if combined with potent CYP3A4 inhibitors
(e.g. protease inhibitors like ritonavir, nelfinavir or indinavir or azole antifungals such as ketoconazole,
macrolide antibiotics, or itraconazole).
- CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine may decrease
buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence
with buprenorphine. It is recommended that patients receiving buprenorphine should be closely monitored
if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of
buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.
- Concomitant use of 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
Buprenorphine is a CYP3A4 inhibitor in vitro. The risk of inhibition in vivo at therapeutic concentrations
seems low, although it cannot be excluded. When buprenorphine is combined with CYP3A4 substrates
the plasma levels of these substrates may increase and dose-dependent side effects may appear.
Buprenorphine does not inhibit CYP2C19 in vitro. The inhibitory effect of buprenorphine on other
enzymes capable of metabolising substrates in medicinal products has not been studied.
4.6 Fertility, pregnancy and lactation
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.
Towards 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 (e.g. hypertonia, neonatal tremor, neonatal agitation,
myoclonus or convulsions). The syndrome is generally delayed for several hours to several days after
Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at
the end of pregnancy, to prevent the risk of respiratory depression or withdrawal syndrome in neonates.
Furthermore, the use of buprenorphine during pregnancy should be assessed by the physician.
Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk
to the fetus.
Buprenorphine and its metabolites are excreted in human milk. As evidenced in rats, buprenorphine has
the potential to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with
There are no data on the effects of buprenorphine on human fertility. Animal studies have shown a
reduction in female fertility at high doses (see section 5.3).
4.7 Effects on ability to drive and use machines
Buprenorphine has minor to moderate influence on the ability to drive and use machines when
administered to opioid dependent patients. This may cause drowsiness, dizziness or impaired thinking,
especially during treatment induction and dose adjustment. When taken together with alcohol or central
nervous system depressants, the effect is likely to be more pronounced (see section 4.4 and 4.5).
Therefore, caution is advised when driving or operating hazardous machinery in case buprenorphine may
affect their ability to engage in such activities.
This medicine can affect your ability to drive.
Do not drive whilst taking this medicine until you know how this medicine affects you.
It may be an offence to drive if your ability to drive safely is 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
Summary of the safety profile
The most commonly reported treatment related adverse reaction reported during the pivotal clinical trials
were constipation and symptoms commonly associated with opioid withdrawal (i.e. insomnia, headache,
nausea, hyperhidrosis and pain). Some reports of seizure, vomiting, diarrhoea, and elevated liver function
tests were considered serious.
Tabulated list of adverse reactions
The onset of undesirable effects depends on the patient's tolerance threshold, which is higher in drug
addicts than in the general population. The frequency of possible side-effects listed below is defined using
the following convention.
Very common (≥1/10)
Common (≥1/100 to ≤1/10)
Uncommon (≥1/1000 to ≤1/100)
Rare: (≥1/10000 to ≤1/1000)
Very rare: (≤1/10000)
Table 1: List of adverse reactions reported on the use of buprenorphine
Undesirable effects observed in clinical studies and observation
System Organ Class
Immune system disorders
Nervous system disorders
Respiratory, thoracic and
Renal and Urinary disorders
Skin and subcutaneous tissue
Musculoskeletal and connective
Infections and Infestations
Urinary tract infection,
Blood and Lymphatic system
Metabolism and nutrition
Reproductive system and breast
Drug withdrawal syndrome
Liver function test abnormal,
Blood creatinine increased
Injury, poisoning and procedural
The most common adverse drug reactions reported during post-marketing surveillance are captured in
Description of other selected adverse reactions observed post-marketing
The following is a summary of other post-marketing adverse event reports that are considered serious or
otherwise noteworthy, some of which may have only been observed with buprenorphine alone in the
treatment of opioid dependence:
In cases of intravenous drug misuse, local reactions, sometimes septic (abscess, cellulitis), and
potentially serious acute hepatitis, and other acute infections such as pneumonia, endocarditis have been
reported (see section 4.4).
In patients presenting with marked drug dependence, initial administration of buprenorphine can
produce a drug withdrawal syndrome similar to that associated with naloxone.
The most common signs and symptoms of hypersensitivity include rashes, urticaria and pruritus. Cases
of bronchospasm, respiratory depression, angioedema and anaphylactic shock have been reported (see
Hepatic transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal
syndrome, hepatic encephalopathy and hepatic necrosis have occurred (see section 4.4).
A neonatal drug withdrawal syndrome has been reported among newborns of women who have received
buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from short
acting full µ-opioid agonists. The nature of the syndrome may vary depending upon the mother's drug use
history (see section 4.6).
Hallucination, orthostatic hypotension, syncope and vertigo have been reported.
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 Website:
Symptoms: Respiratory depression as a result of central nervous system depression is the primary
symptom requiring intervention in the case of overdose because it may lead to respiratory arrest and
death. Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting
and/or speech disorders.
Treatment: general supportive measures should be instituted, including close monitoring of respiratory
and cardiac status of the patient. 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
If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Use of an opioid antagonist (e.g. 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 Espranor should be taken into consideration when determining
length of treatment needed to reverse the effects of an overdose. Naloxone can be cleared more rapidly
than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms, so
a continuing infusion may be necessary. If infusion is not possible, repeat dosing with naloxone may be
required. The naloxone dose may range up to 2 mg and be repeated every 2-3 minutes until a satisfactory
response is achieved, but should not exceed a 10 mg starting dose. Ongoing IV infusion rates should be
titrated to patient response.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07BC01
The Espranor oral lyophilisate dosage form is designed to rapidly disperse on the tongue usually in less
than 15 seconds.
Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the μ (mu) and κ (kappa)
receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible
link with the μ receptors which, over a prolonged period, minimises the need of the addicted patient for
During clinical pharmacological studies in opiate-dependent subjects, buprenorphine demonstrated a
ceiling effect on a number of parameters, including positive mood, “good effect”, and respiratory
5.2 Pharmacokinetic properties
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and
glucuroconjugation in the small intestine and liver. The use of this medication by the oral route is
Peak plasma concentrations are achieved around 70 minutes after oromucosal administration and the
maximal dose-concentration relationship is linear, between 2 mg and 8 mg.
The absorption of buprenorphine is followed by a rapid distribution phase and a distribution half-life of 2
to 5 hours.
Biotransformation and elimination
Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule and
the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-dealkylation of
buprenorphine. N-dealkylbuprenorphine (also known as norbuprenorphine) is a μ (mu) agonist with weak
Elimination of buprenorphine is bi- or tri- exponential, and has a mean half-life from plasma of 32 hours.
Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites
(70%), the rest being eliminated in the urine.
5.3 Preclinical safety data
Pre-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeat dose toxicity, genotoxicity or carcinogenicity.
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 (5
mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal
Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs
following 52 weeks of oral dosing of 75 mg/kg/day.
6. Pharmaceutical particulars
6.1 List of excipients
Mint flavour (051296 TP0551)
Anhydrous citric acid
6.3 Shelf life
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in the original
package (blister) to protect from light and moisture.
6.5 Nature and contents of container
Unit dose blisters composed of PVC/OPA/Al/OPA/PVC film with Al/PET/paper lidding with 7 or 28 oral
lyophilisates, in a cardboard carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local
7. Marketing authorisation holder
Martindale Pharmaceuticals Ltd
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text
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