Espranor 2mg oral lyophilisates

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Buprenorphine hydrochloride
Available from:
Martindale Pharmaceuticals Ltd
ATC code:
N07BC01
INN (International Name):
Buprenorphine hydrochloride
Dosage:
2mg
Pharmaceutical form:
Oral lyophilisate
Administration route:
Oromucosal
Class:
Schedule 3 (CD No Register)
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04100300; GTIN: 5026468198122 5026468198825
Authorization number:
PL00156/0364

Read the complete document

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

symptoms.

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

symptoms.

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

(hallucination)

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

withdrawal syndrome.

Common side effects (may effect up to 1 in 10

people) are:

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

people) are:

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

take Espranor

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

take it)

You are allergic (hypersensitive) to buprenorphine

or any of the other ingredients in Espranor (see

section 6)

Warnings and Precautions

Talk to your doctor, pharmacist or nurse before

taking Espranor:

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

breathe).

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

Espranor:

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

saquinavir

Phenprocoumon (a blood thinning medicine)

If you are taking any of the following medicines,

your doctor may need to prescribe a higher dose of

Espranor:

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

withdrawal.

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://

www.gov.uk/drug-driving-law.

Talk to your doctor or pharmacist if you are not sure

whether it is safe for you to drive while taking this

medicine

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

appear.

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

methadone.

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

treatment with.

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

perforated lines.

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.

are:

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

Website: http//www.mhra.gov.uk/yellowcard.

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

children

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

storage conditions.

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

information

What Espranor contains:

The active substance is buprenorphine (as

buprenorphine hydrochloride). Each oral

lyophilisate (wafer) contains 2 mg or 8 mg of

buprenorphine.

The other ingredients are gelatin, mannitol,

aspartame, mint flavour and citric acid.

What Espranor looks like and the contents of the

pack

Espranor 2 mg oral lyophilisate is a white to off-white

circular oral lyophilisate (wafer) marked with “M2” on

one side.

Espranor 8 mg oral lyophilisate is a white to off-white

circular oral lyophilisate (wafer) marked with “M8” on

one side.

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

Bampton Road

Harold Hill

Romford, Essex

RM3 8UG

United Kingdom.

Manufacturer - Batch Release Site:

Macarthys Laboratories Limited

T/A Martindale Pharma

Bampton Road

Harold Hill

Romford,

Essex, RM3 8UG

United Kingdom

This medicinal product is authorised in the Member

states of the EEA under the following names:

United Kingdom

Espranor 2 mg oral lyophilisate

Espranor 8 mg oral lyophilisate

Sweden

Espranor 2 mg frystorkad tablett

Espranor 8 mg frystorkad tablett

Malta

Espranor 2 mg oral lyophilisate

Espranor 8 mg oral lyophilisate

This leaflet was last updated in March 2017

Reference Number:

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

D03823

Espranor 2 mg Oral Lyophilisate

Espranor 8 mg Oral Lyophilisate

(Buprenorphine)

Continued overleaf

100mm Measurement Verification Bar

D03823

3823-A

Espranor is not interchangeable with other oral

buprenorphine products and the dose of Espranor

may differ from the dose of other buprenorphine

products

Take Espranor by placing ON your tongue, not

under your tongue.

Read the complete document

Object 1

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

Oral lyophilisate.

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

psychological treatment.

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

dependence/addiction.

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

effect.

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

symptoms.

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

patient's requirement.

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.

Elderly

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.

Paediatrics

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.

4.3 Contraindications

- 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

Warnings

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.

Diversion:

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.

Precipitated Withdrawal:

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

breath).

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 impairment

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 impairment

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).

CNS depression

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.

Paediatric population

Espranor is not recommended for use in children below age 15 years due to lack of data on safety and

efficacy.

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

concomitant disease.

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

hazardous.

- 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

are declining.

- 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

symptoms.

- 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

been reported.

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

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.

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

birth.

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.

Breastfeeding

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

Espranor.

Fertility

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

Table

Undesirable effects observed in clinical studies and observation

studies

System Organ Class

Frequency

Adverse Event

Immune system disorders

Uncommon:

Hypersensitivity

Psychiatric disorders

Very common:

Insomnia

Common:

Anxiety, Depression,

Libido decreased,

Nervousness,

Thinking abnormal

Uncommon:

Abnormal dreams,

Agitation,

Apathy,

Depersonalisation,

Drug dependence,

Euphoric mood,

Hostility

Nervous system disorders

Very common:

Headache

Common:

Migraine,

Dizziness,

Hypertonia,

Paraesthesia,

Somnolence

Uncommon:

Amnesia,

Convulsion,

Hyperkinesia,

Speech disorder,

Tremor

Eye disorders

Common:

Amblyopia,

Lacrimation

Uncommon:

Conjunctivitis,

Miosis

Vascular disorders

Common:

Hypertension,

Vasodilatation

Uncommon:

Hypotension

Respiratory, thoracic and

mediastinal disorders

Common:

Cough

Uncommon:

Asthma,

Dyspnoea,

Yawning

Gastrointestinal disorders

Very common:

Constipation,

Nausea

Common:

Abdominal Pain,

Diarrhoea,

Dyspepsia,

Flatulence,

Vomiting,

Oral hypoaesthesia

Uncommon:

Mouth ulceration,

Tongue discolouration

Renal and Urinary disorders

Common:

Urine Abnormality

Uncommon:

Albuminuria,

Dysuria,

Haematuria,

Nephrolithiasis,

Urinary retention

Skin and subcutaneous tissue

disorders

Very common:

Hyperhidrosis (Sweating)

Common:

Pruritus,

Rash,

Urticaria

Uncommon:

Acne,

Alopecia,

Dermatitis exfoliative,

Dry skin,

Skin mass

Musculoskeletal and connective

tissue disorders

Common:

Back Pain

Arthralgia

Muscle spasms

Myalgia

Uncommon:

Arthritis

Infections and Infestations

Common:

Influenza,

Infection,

Pharyngitis,

Rhinitis

Uncommon:

Urinary tract infection,

Vaginal infection

Blood and Lymphatic system

disorders

Uncommon:

Anaemia,

Leukocytosis,

Leukopenia,

Lymphadenopathy,

Thrombocytopenia

Metabolism and nutrition

disorders

Uncommon:

Decreased appetite,

Hyperglycaemia,

Hyperlipidaemia,

Hypoglycaemia

Cardiac disorders

Common:

Palpitations

Uncommon:

Angina Pectoris,

Bradycardia,

Myocardial infarction,

Tachycardia

Reproductive system and breast

disorders

Common:

Erectile dysfunction

Uncommon:

Amenorrhoea,

Ejaculation disorder,

Menorrhagia,

Metrorrhagia

General disorders

Very common:

Drug withdrawal syndrome

Common:

Asthenia,

Chest Pain,

Chills,

Pyrexia,

Malaise,

Pain,Oedema peripheral

Uncommon:

Hypothermia

Investigations

Common:

Liver function test abnormal,

Weight decreased

Uncommon:

Blood creatinine increased

Injury, poisoning and procedural

complications

Common:

Injury

Uncommon:

Heat Stroke

The most common adverse drug reactions reported during post-marketing surveillance are captured in

Table 1.

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

section 4.8).

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:

http://www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

are available.

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

drugs.

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

depression.

5.2 Pharmacokinetic properties

Absorption

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

therefore inappropriate.

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.

Distribution

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

intrinsic activity.

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

mortality.

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

Gelatin

Mannitol

Aspartame (E951)

Mint flavour (051296 TP0551)

Anhydrous citric acid

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

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

requirements.

7. Marketing authorisation holder

Martindale Pharmaceuticals Ltd

Bampton Road

Romford

Essex

RM3 8UG

United Kingdom

8. Marketing authorisation number(s)

PL00156/0364

9. Date of first authorisation/renewal of the authorisation

22/06/2015

10. Date of revision of the text

July 2017

Company Contact Details

Martindale Pharma

Address

Bampton Road, Harold Hill, Romford, Essex, RM3 8UG

Telephone

+44 (0)1277 266 600

Medical Information e-mail

[email

protected]

http://www.martindalepharma.co.uk

+44 (0)1277 848 976

Customer Care direct line

+(0)800 137 627

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