By-Madol SR 150 mg prolonged-release capsules, hard

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Tramadol hydrochloride
Available from:
Ethypharm
ATC code:
N02AX; N02AX02
INN (International Name):
Tramadol hydrochloride
Dosage:
150 milligram(s)
Pharmaceutical form:
Prolonged-release capsule, hard
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Other opioids; tramadol
Authorization status:
Not marketed
Authorization number:
PA0549/016/003
Authorization date:
2006-10-27

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Package Leaflet: Information for the user

BY-MADOL SR 150 mg prolonged-release capsules, hard

Tramadol hydrochloride

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.

What is in this leaflet

What By-Madol SR is and what it is used for

What you need to know before you take By-Madol SR

How to take By-Madol SR

Possible side effects

How to store By-Madol SR

Contents of the pack and other information

1.

What By-Madol SR is and what it is used for

Tramadol hydrochloride – the active substance of By-Madol SR –belongs to a group of medicines

known as opioid analgesics or painkillers. Its pain-relieving action is due to its effect on specific nerve

cells in the spinal cord and brain.

By-Madol SR is used in the treatment of moderate to severe pain.

2.

What you need to know before you take By-Madol SR

Do not take By-Madol SR:

if you are allergic to tramadol or any of the other ingredients of this medicine (listed in sec-

tion 6).

if you are intoxicated with alcohol or with sedative drugs include sleeping pills, other pain-

killers or psychotropic medicines (medicines that affect mood and emotions)

if you are taking, or have taken in the last two weeks, certain medicines called “monoamine oxi-

dase inhibitors” or MAOIs (used to treat depression). The combination could result in a serious,

potentially life threatening interaction (see “Other medicines and By-Madol SR”)

if you have epilepsy that is not controlled with your current medicine

By-Madol SR is not suitable as a drug substitute for the treatment of drug addiction.

By-Madol SR is contraindicated in children below 12 years of age.

Warnings and Precautions

Talk to your doctor, pharmacist or nurse before taking By-Madol SR;

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if you think that you are addicted to other pain relievers (opioids);

if you suffer from consciousness disorders (if you feel that you are going to faint);

if you are in a state of shock (cold sweat may be a sign of this);

if you suffer from epilepsy or seizures (fits) or have had them in the past, because tramadol

could increase the risk of you having further fits.

if you have liver or kidney problems.

Tramadol is transformed in the liver by an enzyme. Some people have a variation of this enzyme and

this can affect people in different ways. In some people, they may not get enough pain relief but other

people are more likely to get serious side effects. If you notice any of the following side effects, you

must stop taking this medicine and seek immediate medical advice: slow or shallow breathing, confu-

sion, sleepiness, small pupils, feeling or being sick, constipation, lack of appetite.

Epileptic fits have been reported in patients taking tramadol at the recommended dose level. The risk

may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg).

As with all opioids, tramadol should be used with caution, and only under medical supervision in seri-

ously ill patients including those with impaired breathing, excessively low blood pressure (shock),

serious head injury or brain diseases that may cause elevated pressure in the skull.

As with all opioids, tramadol may lead to psychological and physical dependence or addiction in some

people, especially with long term use. The dose needed to achieve the desired effect may increase with

time. Tramadol should be used with caution, and only for short periods, in patients who are addicted to

other opioid pain-killers.

Children and adolescents

Use in children with breathing problems

Tramadol is not recommended in children with breathing problems, since the symptoms of tramadol

toxicity may be worse in these children.

Other medicines and Tramadol Ehtypharm

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The pain-relieving effect of By-Madol SR may be weakened and/or shortened if you also take medi-

cines containing:

carbamazepine (used to treat epilepsy)

pentazocine, nalbuphine or buprenorphine (pain killers)

ondansetron (used to stop you feeling sick).

Your doctor will tell you whether you should take By-Madol SR, and which dose.

The risk of side effects increases,

if you are taking medicines which may cause convulsions (fits), such as certain antidepressants or

antipsychotics. The risk having a fit may increase if you take By-Madol SR at the same time.

Your doctor will tell you whether By-Madol SR is suitable for you.

if you are taking certain antidepressants. By-Madol SR may interact with these medicines and

you may experience symptoms such as involuntary, rhythmic contractions of muscles, including

the muscles that control movement of the eye, agitation, excessive sweating, tremor,

exaggeration of reflexes, increased muscle tension, body temperature above 38 °C.

if you take By-Madol SR at the same time as sedative medicines such as tranquillizers or sleep-

ing pillsand other pain relievers (morphine, codeine – also as cough medicine). You may feel

excessively drowsy or feel that you might faint. If it happens tell your doctor.

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if you take By-Madol SR at the same time as alcohol. Tramadol may increase the intoxicating

effect of alcohol and therefore you should be cautious if you wish to drink alcohol during

treatment with By-Madol SR.

if you take By-Madol SR at the same time as medicines that inhibit blood clotting, such as war-

farin. The dose of these medicines may need to be reduced, otherwise there could be an in-

creased risk of potentially serious bleeding.

Do not take By-Madol SR at the same time as medicines called “monoamine oxidase inhibitors”

(which are used to treat depression), or if you have taken one in the past 2 weeks.

Concomitant use of By-Madol SR and sedative medicines such as benzodiazepines or related drugs

increases the risk of drowsiness, difficulties in breathing (respiratory depression), coma and may be

life-threatening. Because of this, concomitant use should only be considered when other treatment

options are not possible.

However if your doctor does prescribe By-Madol SR together with sedative medicines the dose and

duration of concomitant treatment should be limited by your doctor.

Please tell your doctor about all sedative medicines you are taking, and follow your doctor’s dose

recommendation closely. It could be helpful to inform friends or relatives to be aware of the signs and

symptoms stated above. Contact your doctor when experiencing such symptoms.

By-Madol SR with food and alcohol

Do not drink alcohol during treatment with By-Madol SR as its effect may be intensified.

Food does not influence the effect of By-Madol SR.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

By-Madol SR may affect an unborn child. Therefore it should not be taken during pregnancy.

Tramadol is excreted into breast milk. For this reason, you should not take By-Madol SR more than

once during breast-feeding, or alternatively, if you take By-Madol SR more than once, you should stop

breast-feeding.

Based on human experience tramadol is suggested not to influence female or male fertility.

Driving and using machines

By-Madol SR may cause side effects such as drowsiness and blurred vision. If this happens, do not

drive or use any tools/ machines and do not perform any hazardous tasks.

By-Madol SR contains benzoates and sucrose

This medicine contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may

cause allergic reactions, some of which may be delayed.

This medicine contains sucrose. If you have been told by your doctor that you have an intolerance to

some sugars, contact your doctor before taking this medicine.

By-Madol SR contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per prolonged-release capsule, that is to say

essentially ‘sodium-free’.

3.

How to take By-Madol SR

The dosage should be adjusted to the intensity of your pain and your individual pain sensitivity.

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In general the lowest pain-relieving dose should be taken.

Always take By-Madol SR exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The usual doses are given below. Your doctor may gradually increase or decrease your dose

depending on how you respond to the treatment.

Adults and adolescents aged 12 and over:

The usual dose is one 150mg-capsule taken twice a day, equivalent to 300 per day. The capsules

should be taken in the morning and evening. You should not normally take more than 400 mg a day.

Use in children:

This medicinal product is not suitable for use in children below 25 kg body weight which in general

does not allow for individualized dosage in children below 12 years of age. Other form(s) of this medi-

cine may be more suitable for children; ask your doctor, pharmacist or nurse.

Elderly patients:

In elderly patients (above 75 years) the excretion of tramadol may be delayed. If this applies to you,

your doctor may recommend prolonging the dosage interval.

Severe liver or kidney disease (insufficiency)/dialysis patients:

Patients with severe liver and/or kidney problems, should not take By-Madol SR.

If in your case the insufficiency is mild or moderate, your doctor may may recommend prolonging the

dosage interval.

Route and method of administration

For oral use

The capsules should be swallowed whole with a glass of water.

The capsules can be taken with or without food. They should NOT be chewed, divided or crushed.

How long should you take By-Madol SR

You should not take By-Madol SR

for longer than necessary. If you need to be treated for a longer period,

your doctor will check at regular short intervals (if necessary with breaks in treatment) whether you

should continue to take By-Madol SR

and at what dose.

If you have the impression that the effect of By-Madol SR

is too strong or too weak, talk to your doctor or

pharmacist.

If you take more By-Madol SR than you should

If high doses are taken accidentally, you should contact your doctor immediately or go to your nearest

hospital casualty department. A number of symptoms may occur. These might include: very small

pupils, vomiting (being sick), a fall in blood pressure, a fast heartbeat, collapse, fainting or even coma,

epileptic fits and difficulties in breathing or shallow breathing.

If you forget to take By-Madol SR

, take it as soon as you remember and then carry on as before. Do

not take a double dose to make up for a forgotten dose.

If you stop taking By-Madol SR

, your pain may return.

You should not suddenly stop taking this medicine unless your doctor tells you to. If you want to stop

taking your medicine, discuss this with your doctor first, particularly if you have been taking it for a

long time. Your doctor will advise you when and how to stop, which may be by lowering the dose

gradually to reduce the chance of developing unnecessary side effects (withdrawal symptoms).

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If you have been taking this medicine for a very long time, you may get the following side effects if

you suddenly stop treatment: restlessness, anxiety, nervousness, shaking or an upset stomach. Very few

people may get panic attacks, hallucinations, unusual perceptions such as itching, tingling and

numbness, and “ringing” in the ears (tinnitus). Further unusual CNS symptoms, i.e. confusion,

delusions, change of perception of the own personaility (depersonalisation), and change in perception

of reality (derealisation) and delusion of persecution (paranoia) have been seen very rarely. If you get

any of these effects after stopping treatment with By-Madol SR please talk to your doctor.

If you have any further questions on the use of this product, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

By-Madol SR can occasionally cause allergic reactions although serious allergic reactions (including

anaphylaxis and angioedema) are rare. Tell your doctor immediately if you get any sudden

wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially

affecting your whole body).

The following side effects may occur:

Very common: may affect more than 1 in 10 people

Feeling sick (nausea)

Dizziness

Common: may affect up to 1 in 10 people

Headache

Being sick (vomiting)

Constipation

Fatigue (tiredness)

Drowsiness

Dry mouth

Sweating (hyperhidrosis)

Uncommon: may affect up to 1 in 100 people

Effects on the heart and blood circulation

(pounding of the heart, fast heartbeat, feel-

ing faint or collapse). These adverse effects

may particularly occur in patients in an up-

right position or under physical strain.

Urge to be sick (retching)

Stomach trouble (e.g. feeling pressure in

the stomach, bloating, diarrhoea)

Skin reactions (e.g. itchiness, rash,

sudden onset of skin redness)

Rare: may affect up to 1 in 1,000 people

Slow heartbeat

Increased in blood pressure

Changes in appetite

Abnormal sensations (e.g. itching, tin-

gling,

numbness),

trembling,

epileptic

fits,

muscle

twitches,

uncoordinated

movement,

transient loss of conscious-

ness (syncope), speech disorders

Slow

breathing,

shortness

breath

(dyspnoea)

Epileptic (“fits”) have occurred mainly

at high doses of tramadol or when tra-

madol was taken at the same time as

Psychological complaints may appear after

treatment with By-Madol SR. Their inten-

sity and nature may vary (according to the

patient’s personality and length of therapy).

These may appear as a change in mood

(mostly high spirits, occasionally irritated

mood), changes in activity (slowing down

but sometimes an increase in activity) and

decreased cognitive and sensory perception

(being less aware and less able to make de-

cisions, which may lead to errors in judge-

ment).

Hallucinations, confusion, sleep disor-

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other medicines which may induce fits.

Uncoordinated movement

ders, delirium, anxiety and nightmares

Blurred vision, excessive dilation of the

pupils (mydriasis), constriction of the

pupil (miosis)

Weak muscles

Passing less urine than normal (dysuria)

or passing urine with difficulty or pain

Drug dependence may occur

Psychological complaints may appear

after treatment with By-Madol SR.

Their intensity and nature may vary (ac-

cording to the patient’s personality and

length of therapy). These may appear as

a change in mood (mostly high spirits,

occasionally irritated mood), changes in

activity (slowing down but sometimes

an increase in activity) and decreased

cognitive and sensory perception (being

less aware and less able to make deci-

sions, which may lead to errors in

judgement).

Worsening of asthma has been reported,

however it has not been established

whether it was caused by tramadol. If

the recommended doses are exceeded,

or if other medicines that depress brain

function are taken at the same time,

breathing may slow down.

Allergic reactions (e.g. difficulty in

breathing, wheezing, swelling of skin)

and shock (sudden circulation failure)

have occurred in very rare cases.

Very rare: may affect up to 1 in 10,000 people

Increased levels of liver enzymes

Not known:frequency cannot be estimated from the available data

Decrease in blood sugar level (hypoglycaemia)

When treatment is stopped abruptly, signs of withdrawal may appear (see “If you stop taking By-Madol

SR”).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website www.hpra.ie,

e-mail: medsafety@hpra.ie. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store By-Madol SR

Keep this medicine out of the sight and reach of children.

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Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP.

The expiry date refers to the last day of that month.

Do not store above 25°C.

Do not throw away any medicines via wastewater of 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 By-Madol SR

contains

The active substance is tramadol hydrochloride. Each capsule contains 150 mg of tramadol hydro-

chloride equivalent to 131.73 mg tramadol.

The other ingredients are:

Sugar spheres (maize starch and sucrose)

Macrogol 4000

Polyacylate dispersion 30% (ethyl acrylate, methyl methacrylate, nonoxynol)

Dimeticone

emulsion

(dimethicone,

(t-octylphenoxy)polyethoxyethanol,

Macrogol

600,

polyethylene-sorbitan-monolaurate,

sodium

benzoate,

propyl-4-hydroxybenzoate

(E216),

methyl-4-hydroxybenzoate (E218), propylene glycol, sorbic acid)

Hypromellose

Talc

Gelatin

Titanium dioxide (E 171)

Yellow iron oxide (E172).

What By-Madol SR looks like and contents of the pack

Opaque yellow gelatin capsules containing white spherical microgranules (“beads”)

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 100 capsules

Hospital packs: 500 capsules

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

ETHYPHARM SA

194 Bureaux de la Colline

Bâtiment D

92213 Saint-Cloud cedex

France

Manufacturer

ETHYPHARM

Chemin de la Poudrière

76120 Grand Quevilly

FRANCE

TOLL MANUFACTURING SERVICES, S.L.

C/Aragoneses 2

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28108 Alcobendas (Madrid)

Spain

FERRER INTERNACIONAL, S.A.

Joan Buscallá, 1-9

08173 Sant Cugat del Valles

(Barcelona) Spain

CHIESI Limited

Cheadle Royal Business Park

Highfield, Cheadle, SK8 3GY

United Kingdom

This medicinal product is authorised in the Member States of the EEA under the following names:

Germany: Tramadol Ethypharm 150 mg

Ireland: By-Madol SR 150 mg

Portugal: Gelotralib 150 mg

Spain: Gelotradol 150 mg

United-Kingdom: Maxitram SR 150 mg

This leaflet was last revised in: July 2019

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

By-Madol SR 150 mg prolonged-release capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 prolonged-release capsule contains 150 mg of tramadol hydrochloride equivalent to 131.73 mg tramadol.

Excipients with known effects:

0.011 mg Methyl parahydroxybenzoate/prolonged-release capsule

0.0034 mg Propyl parahydroxybenzoate/prolonged-release capsule

16.05 mg Sucrose/prolonged-release capsule

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release capsule, hard

Capsules with opaque yellow cap and body, containing white spherical microgranules

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

For moderate to severe pain.

4.2 Posology and method of administration

Posology:

The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose

for analgesia should generally be selected.

Adults and adolescents aged 12 years and over:

150 mg tramadol hydrochloride twice daily (corresponding to 300 mg of tramadol hydrochloride/day), morning and evening

administration recommended.

The smallest effective analgesic dose should always be used. Daily doses of 400 mg of active substance must not be exceeded,

unless exceptional medical reasons require so. A minimum interval of 8 hours must be respected between administrations.

Paediatric population

By-Madol SR is not suitable for use in children below 25 kg body weight which in general does not allow for individualized

dosage in children below 12 years of age. Consequently, a more suitable form of administration should be used.

Geriatric patients

A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency.

In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended

according to the patient's requirements.

Renal insufficiency/dialysis and hepatic impairment

In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the

dosage intervals should be carefully considered according to the patient's requirements. In cases of severe renal and/or severe

hepatic insufficiency By-Madol SR is not recommended.

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Note:

The recommended dosages are indicative only. In general, the smallest effective analgesic dose should be used. For the

treatment of chronic pain, a pre-established posology must be respected.

For doses not realisable/practicable with this medicinal product other strengths of this medicinal product or other

pharmaceutical forms and products are available.

Method of administration

The prolonged-release capsule, hard, must be swallowed whole with sufficient liquid, irrespective of mealtimes.

By-Madol SR must never be used for longer than therapeutically absolutely necessary. Should prolonged pain treatment

according to the nature and severity of the illness be necessary, a careful evaluation should be carried out at short regular

intervals (if necessary by instituting treatment pauses) to check whether or to what extent prolonged treatment is medically

necessary.

4.3 Contraindications

By-Madol SR must not be used in the following cases:

hypersensitivity to tramadol or to any of the excipients listed in section 6.1;

acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;

patients who are taking monoamine oxidase inhibitors or have been taking them within the previous two weeks

(see section 4.5);

epilepsy uncontrolled by treatment.

By-Madol SR must not be used for the treatment of opioid dependence.

By-Madol SR 50 mg is not suitable for use in children under 25 kg body weight (see also section 4.2).

This medicinal product is contraindicated in children below 12 years of age.

4.4 Special warnings and precautions for use

By-Madol SR should only be used following a strict benefit-risk evaluation and appropriate precautionary measures in the

following cases:

opioid-dependent patients,

impaired consciousness of unclear aetiology, shock

impaired respiratory centre or function,

increased intracranial pressure, head injury, or brain disease,

impaired liver or kidney function

The medicinal product should be used with caution in patients showing sensitivity reactions to opiates.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being

administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of

respiratory depression cannot be excluded in these situations.

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related active substances

Concomitant use of tramadol and sedative medicinal products such as benzodiazepines or related active substances may result

in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative

medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is

made to prescribe By-Madol SR concomitantly with sedative medicinal products, the lowest effective dose should be used, and

the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is

strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

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Convulsions have been reported in patients taking tramadol at the recommended dosage. Increased risk may be associated

with the administration of doses exceeding the recommended daily dose (400 mg). Tramadol can increase the risk of

convulsions if combined with other medicinal products that lower the convulsion threshold (see section 4.5). Patients with a

history of epilepsy or those susceptible to convulsions should only be treated with tramadol if there are compelling

circumstances.

Patients may develop tolerance, and psychic and physical dependence, especially after long-term use. At therapeutic doses,

withdrawal symptoms have been reported with a frequency of 1 in 8,000. In patients with a tendency to drug abuse or drug

dependence, treatment with By-Madol SR should only be for short periods and under strict medical supervision.

When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms

of withdrawal.

By-Madol SR is not suitable for use as a substitute in opioid-dependent patients. Although it is an opiate agonist, tramadol

cannot suppress morphine withdrawal symptoms.

CYP2D6 metabolism

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an

adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this

deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even

at commonly prescribed doses.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting,

constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which

may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are

summarised below:

Population

African/Ethiopian

African American

Asian

Caucasian

Greek

Hungarian

Northern European

Prevalence %

3.4% to 6.5%

1.2% to 2%

3.6% to 6.5%

6.0%

1.9%

1% to 2%

Post-operative use in children

There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or

adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be

exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close

monitoring for symptoms of opioid toxicity including respiratory depression.

Children with compromised respiratory function

Tramadol is not recommended for use in children in whom respiratory function might be compromised including

neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or

extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.

The medicinal product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic

reactions (possibly delayed).

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucosegalactose

malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

By-Madol SR contains less than 1 mmol sodium (23 mg) per prolonged-release capsule, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

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Tramadol should not be combined with MAO inhibitors (see section 4.3).

Life-threatening interactions affecting the central nervous system as well as respiratory and cardiovascular function have been

observed in patients who had been treated with MAO inhibitors within 14 days prior to the administration of the opioid

pethidine. The same interactions with By-Madol SR as with MAO inhibitors cannot be ruled out.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs),

serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure

threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs),

serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and

mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed:

Spontaneous clonus

Inducible or ocular clonus with agitation or diaphoresis

Tremor and hyperreflexia

Hypertonia and body temperature> 38°C and inducible or ocular clonus.

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity

of the symptoms.

The concurrent administration of By-Madol SR with other centrally acting drugs, including alcohol, may mutually potentiate

effects on the CNS (see section 4.8).

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of

sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of

concomitant use should be limited (see section 4.4).

Based on available pharmacokinetic results, no clinically relevant interactions are expected with the co-administration or

previous administration of tramadol with cimetidine (enzyme inhibitor). Concurrent or previous treatment with carbamazepine

(enzyme inducer) may reduce and shorten the analgesic effect.

The combination of a mixture of agonists/antoganists (e.g., buprenorphine, nalbuphine, pentazocine) and tramadol is not

recommended, since there is a theoretical possibility that the analgesic effect of a pure agonist becomes decreased in such

conditions.

Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to

reports of increased INR with major bleeding and ecchymoses in some patients.

In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT

antagonist ondansetron increased

the requirement of tramadol in patients with postoperative pain.

Other CYP3A4 inhibitors, such as ketoconazole and erythromycin may inhibit both the metabolism of tramadol (N

demethylation) and possibly also the metabolism of the active O-demethylated metabolites. The clinical significance of this

interaction is not known.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality.

Tramadol crosses the placenta.

Insufficient experience is available on the chronic use of tramadol during pregnancy. The repeated administration of tramadol

during pregnancy can lead to increased tolerance of tramadol in the foetus and consequently to withdrawal symptoms in the

new-born infant after birth. For this reason By-Madol SR should not be used during pregnancy.

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Tramadol administered before or during birth does not affect uterine contractility. In new-born infants it may induce

respiratory rate changes which normally are not clinically significant.

Breast-feeding

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for

maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3%

of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively,

breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not

necessary following a single dose of tramadol.

Fertility

Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of

tramadol on fertility.

4.7 Effects on ability to drive and use machines

By-Madol SR may cause drowsiness and blurred vision altering one's capacity to react, so that the ability to drive and use

machines or work without a steady foothold is reduced. This applies especially at the start of treatment, when changing over to

another treatment, in combination with other centrally active drugs, and particularly if combined with alcohol.

4.8 Undesirable effects

The most frequent side effects occurring during treatment with By-Madol SR are nausea and vertigo, which occur in more than

1 out of 10 patients.

The reactions are classified according to frequency (very common (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000

to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data)).

Organ System

Frequency

Adverse drug reaction

Metabolism and nutrition disorders

Rare

- change in appetite

Not known

- hypoglycaemia

Psychiatric disorders

Rare

- hallucinations

- confusion

- sleep disturbances

- delirium

- anxiety

- night-mares

Nervous System disorders

Very common

- dizziness

Common

- headaches

- somnolence

Rare

- paraesthesia

- tremor

- epileptiform convulsions

- involuntary muscle contractions,

- abnormal coordination

- syncope

- speech disorders

Eye disorders

Rare

- blurred vision

- miosis

- mydriasis

Cardiac disorders

Uncommon

- effects on cardiovascular regulation: palpitations,

tachycardia

Rare

- bradycardia

- elevated blood pressure

Respiratory, thoracic and mediastinal disorders

Rare

- dyspnea

- respiratory depression

Gastrointestinal disorders

Very common

- nausea

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Common

- vomiting,

- constipation

- dry mouth

Uncommon

- retching, diarrhoea, gastrointestinal discomfort (a

feeling of pressure in the stomach, bloating)

Hepatobiliary disorders

Very rare

- elevated transaminases

Skin and subcutaneous tissue disorders

Common

- hyperhidrosis

Rare

- dermal reactions (e.g., pruritus, rash, urticaria)

Musculoskeletal and connective tissue disorders

Rare

- motorial weakness

Renal and urinary disorders

Rare

- disorders of micturition (dysuria and urinary

retention)

Immune system disorders

Rare

- allergic reactions (e.g., dyspnea, bronchospasm,

wheezing, angioneurotic oedema)

- anaphylaxis

Investigations

Rare

- increased blood pressure

Vascular disordes

Uncommon

- cardiovascular regulation (postural hypotension

or cardiovascular collapse.

General disorders and administration site conditions

Common

- fatigue

For cardiac disorders, adverse reactions may occur especially on intravenous administration and in patients who are physically

stressed.

For vascular disorders, adverse reactions may occur especially on intravenous administration and in patients who are physically

stressed.

For nervous system disorders, convulsions occurred mainly after administration of high doses of tramadol or after concomitant

treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Psychic adverse reactions may occur following administration of tramadol which vary individually in intensity and nature

(depending on personality and duration of treatment). These include changes in mood (e.g. usually elation, occasionally

dysphoria), changes in activity (e.g. usually suppression, occasionally increase), change in cognitive and sensorial capacity (e.g.

decision behaviour, perception disorders).

Drug dependence may occur.

Symptoms of withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation,

anxiety, nervousness, insomnia, hyperkinesias, tremor and gastroinstestinal symptoms. Other symptoms that have very rarely

been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and

unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).

For respiratory disorders, if the recommended doses are considerably exceeded and other centrally depressant substances are

administered concomitantly (see section 4.5), respiratory depression may occur. Worsening of asthma has been reported,

though a causal relationship has not been established.

In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use

of tramadol.

Methyl parahydroxybenzoate and propylparahydroxybenzoate can cause hypersensitivity, even delayed hypersensitivity

reactions.

Reporting of suspected adverse reactions

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this

leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1

6764971, Fax: +353 1 6762517, Website www.hpra.ie, e-mail: medsafety@hpra.ie. By reporting side effects you can help

provide more information on the safety of this medicine.

4.9 Overdose

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Svmptoms

The symptoms of tramadol poisoning are typical of other centrally active analgesics (opioids). In particular, miosis, vomiting,

cardiovascular collapse, impaired consciousness and coma, convulsions and respiratory depression as well as respiratory arrest

may occur.

Management

Depending on symptoms, treatment ordinarily consists of general emergency measures for freeing the airways (beware of

aspiration!) and for maintaining breathing and cardiovascular function. Naloxone can be used as antidote in case of respiratory

depression. Naloxone has been shown to have no effect on convulsions in animal experiments. Intravenous Diazepam should

be used instead.

In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only

recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in

case of intoxication with exceptionally large quantities or prolonged-release formulations.

Tramadol is only slightly dialysable. For this reason, haemodialysis or haemofiltration on their own are not suitable for the

treatment of acute poisoning with By-Madol SR.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, other opioids.

ATC Code: N02AX02

Mechanism of action

Tramadol is a centrally-acting opioid analgesic. It is a non-selective pure agonist at micro t, d, and k opioid receptors with a

higher affinity at the micro receptors. Other mechanisms that contribute to its analgesic effect are inhibition of neuronal

re-uptake of noradrenaline as well as increased serotonin release.

Clinical efficacy and safety

Tramadol has an antitussive effect. In contrast to morphine, tramadol in analgesic doses has no respiratory depression effect

over a wide range and no effect on gastrointestinal motility.

It has only a slight effect on the cardiovascular system. Tramadol potency is given as 1/10 to 1/6 of that for morphine.

Paediatric population

Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000

paediatric patients ranging in age from neonate to 17 years of age. The indications for pain treatment studied in those trials

included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as

other painful conditions likely to require analgesic treatment for at least 7 days.

At single doses of up to 2 mg/kg or multiple doses of up to 8 mg/kg per day (to a maximum of 400 mg per day) efficacy of

tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose

morphine. The conducted trials confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and

paediatric patients older than 1 year (see section 4.2).

5.2 Pharmacokinetic properties

Absorption

Following oral use tramadol absorption is greater than 90%. Absolute average bioavailability is 70%, irrespective of concurrent

food intake. The difference between available absorbed and unmetabolized tramadol can be explained by the fact that there is

only slight first-pass metabolism. First-pass metabolism following oral administration is 30% at most.

Distribution

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Following oral use (100 mg) in liquid form, peak plasma concentrations (C

) after 1.2 hours are calculated to be 309 ± 90

ng/ml and following a similar dose in solid oral form peak plasma concentrations (C

) after 2 hours are 280 ± 49 ng/ml.

Tramadol has high tissue affinity (Vd, β 203 ± 40 1). Serum protein binding is approximately 20%.

Following the administration of By-Madol SR 100 mg peak plasma concentrations (C

) after 4.9 hours are 141 ± 40 ng/ml.

Following the administration of By-Madol SR 200 mg, peak plasma concentrations (C

) after 4.8 hours are 260 ± 62 ng/ml.

Tramadol crosses the blood-brain barrier and the placenta. Very slight amounts of the drug together with its O-demethyl

derivative are found in maternal milk (0.1% and 0.02% of the administered dose, respectively).

Biotransformation

In humans, tramadol is essentially metabolized by N- and O-demethylation as well as by conjugation of the O- demethylation

products with glucuronic acid. Only O-demethyl tramadol is pharmacologically active. There are considerable quantitative

interindividual variations as regards the other metabolites. 11 metabolites have been found in urine to date. According to

results of animal experiments, O-demethyl tramadol exceeds the potency of the parent substance by a factor of 2 to 4. Its

half-life (t½ β) (6 healthy volunteers) is 7.9 hours (ranging between 5.4 to 9.6 hours) and is similar to that of tramadol.

Inhibition of the isoenzymes CYP3A4 and/or CYP2D6 involved in the biotransformation of tramadol can influence the plasma

concentration of tramadol or that of its active metabolites.

Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total

radioactivity of the administered dose. Tramadol half-life may be slightly prolonged in patients with impaired liver or kidney

function. Elimination half-lives of 13.3 ± 4.9 hours (tramadol) and of 18.5 ± 9.4 hours (O-demethyl tramadol) and in extreme

cases of 22.3 and 36 hours, respectively have been determined in patients with cirrhosis of the liver. Elimination half-lives of 11

± 3.2 hours and 16.9 ± 3 hours, and in extreme cases of 19.5 hours and 43.2 hours, respectively have been determined in

patients with renal insufficiency (creatinine clearance < 5 ml/min).

Elimination

The elimination half-life (t½ β) of tramadol is about 6 hours, irrespective of the method of administration. In patients over 75

years of age, elimination half-life may be prolonged by a factor of approx. 1.4.

Linearity/non-linearity

Tramadol at therapeutic doses shows a linear pharmacokinetic profile.

Pharmacokinetic/Pharmacodynamic relationship

The relation between serum concentrations and analgesic effect is dose-dependent while showing significant individual

variations. As a rule, serum concentrations of 100- 300 ng/ml are effective.

Paediatric population

The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple-dose oral administration to

subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight,

but with a higher between-subject variability in children aged 8 years and below.

In children below 1 year of age, the pharmacokinetics of tramadol and O-desmethyltramadol have been investigated, but have

not been fully characterized. Information from studies including this age group indicates that the formation rate of

O-desmethyltramadol via CYP2D6 increases continuously in neonates, and adult levels of CYP2D6 activity are assumed to be

reached at about 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow

elimination and accumulation of O-desmethyltramadol in children under 1 year of age.

5.3 Preclinical safety data

Some in-vitro test systems have indicated mutagenic effects. In vivo tests have given no indications of mutagenic effects.

According to current knowledge tramadol can be classified as a non-mutagenic substance.

Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in the rat and mouse. The rat study gave

no indications of substance-related increases in tumour incidence. In the mouse study, increased incidence of liver cell

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adenoma was observed in the males (dose-dependent, non-significant increases from 15 mg/kg) and an increase in lung

tumours in the females of all dose groups (significant but non-dose dependent increases).

In studies on reproduction toxicity tramadol dosages from 50 mg/kg/day in the rat produced maternal toxic effects and led to

increased neonate mortality. Delayed growth in the form of disorders of ossification and delayed vaginal and eye opening

occurred in the progeny. The fertility of male rats was not impaired. Females on high doses (from 50 mg/kg/day) showed a

reduced gestation index.

From 125 mg/kg maternal toxic effects occurred in rabbits as well as skeletal anomalies in the progeny.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose

Maize starch

Macrogol 4000

Polyacylate dispersion 30% (ethyl acrylate, methyl methacrylate, nonoxynol)

Dimeticone emulsion (dimethicone, (t-octylphenoxy)polyethoxyethanol, Macrogol 600, polyethylene-sorbitan-monolaurate,

sodium benzoate, propyl-para-hydroxybenzoate (E216), methyl-para-hydroxybenzoate (E218), propylene glycol, sorbic acid)

Hypromellose

Talc

Capsule shell:

Gelatin

Titanium dioxide (E 171)

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Aluminium/PVC blisters

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 100 prolonged-release capsules, hard.

Hospital packs: 500 prolonged-release capsules, hard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Ethypharm

194 Bureaux de la Colline - Bâtiment D

92213 Saint-Cloud Cedex

France

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8 MARKETING AUTHORISATION NUMBER

PA0549/016/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27th October 2006

Date of last renewal: 12th July 2011.

10 DATE OF REVISION OF THE TEXT

October 2019

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