Zamadol SR 200mg capsules

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Tramadol hydrochloride
Available from:
CST Pharma Ltd
ATC code:
N02AX02
INN (International Name):
Tramadol hydrochloride
Dosage:
200mg
Pharmaceutical form:
Modified-release capsule
Administration route:
Oral
Class:
Schedule 3 (CD No Register Exempt Safe Custody)
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04070200; GTIN: 5055946801506

Zamadol SR 200mg prolonged-release hard capsules

(tramadol hydrochloride)

Patient Information Leaflet

Read all of this leaflet carefully before you start taking this medicine,

because it contains important information for you.

*

This medicine has been prescribed for you. Do not pass it on to others. It

may harm them, even if their symptoms are the same as yours.

*

Keep this leaflet. You may need to read it again.

*

If you have any further questions, ask your doctor or pharmacist.

*

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

any possible side effects not listed in this leaflet. See section 4.

Your medicine is called Zamadol SR 200mg prolonged-release hard

capsules and will be referred to as Zamadol SR prolonged-release hard

capsules throughout the rest of this leaflet. Please note that the leaflet also

contains information about other strengths of the medicine, Zamadol SR

50mg prolonged-release hard capsules, Zamadol SR 100mg

prolonged-release hard capsules and Zamadol SR 150mg prolonged-release

hard capsules.

What is in this leaflet:

What Zamadol SR prolonged-release hard capsules is and what it is

used for

What you need to know before you take Zamadol SR

prolonged-release hard capsules

How to take Zamadol SR prolonged-release hard capsules

Possible side effects

How to store Zamadol SR prolonged-release hard capsules

Contents of the pack and other information

What Zamadol SR prolonged-release hard

capsules is and what it is used for

Zamadol SR prolonged-release hard capsules belongs to a group of

medicines called analgesics, commonly known as pain killers or pain

relievers. The active substance, tramadol hydrochloride, interrupts the pain

messages being sent to your brain, and it also acts in your brain to stop pain

messages from being felt. This means that Zamadol SR prolonged-release

hard capsules does not stop the pain from happening, but you will not be

able to feel the pain as much.

Zamadol SR prolonged-release hard capsules is used to relieve moderate to

severe pain. (for example, pain after an operation, or after an injury).

What you need to know before you take Zamadol SR

prolonged-release hard capsules

Do not take Zamadol SR prolonged-release hard capsules:

*

if you are allergic to tramadol hydrochloride or to any of the other

ingredients of this medicine (listed in section 6) resulting in a skin rash,

swelling of face or dif culty in breathing

*

if you are taking, or you have taken in the last two weeks, monoamine

oxidase inhibitors (MAOIs) to treat your depression (see section 2,

“Other medicines and Zamadol SR prolonged-release hard capsules”)

*

if you have epilepsy which is not controlled by treatment

*

if you have drunk enough alcohol to make you feel woozy or drunk

*

if you have taken more than prescribed dose of your sleeping tablets,

antipsychotics, antidepressants (antipsychotics and antidepressants

are medicines that affect mood and emotions) or other pain killers, which

can slow down your breathing and reactions.

Warnings and precautions

Talk to your doctor or pharmacist before taking Zamadol SR

prolonged-release hard capsules, if:

*

you have had an allergic reaction to any morphine-like medicines.

*

you have been taking Zamadol SR prolonged-release hard capsules or

any other tramadol containing medicine for a long time.

*

you are addicted to morphine.

*

you have severe problems with your liver or kidneys.

*

you have recently had a head injury or have a very bad headache that

makes you sick.

*

you have ever had convulsions (fits) or do you suffer from epilepsy.

*

you have asthma or trouble breathing.

*

you are going to have surgery requiring a general anaesthetic.

There is rare possibility that Zamadol SR prolonged-release hard capsules

may cause convulsions (fits). The risk is increased if doses above

the daily maximum are taken and if you are also taking anti-depressants or

antipsychotics.

You have a tendency to drug addiction or abuse you should take Zamadol

SR prolonged-release hard capsules for short periods only. Please

tell your doctor about this as he/she may want to monitor your pain control

more closely.

You should not take this product for the treatment of withdrawal symptoms, if

you are addicted to drugs.

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, confusion,

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

Children and adolescents:

Zamadol SR prolonged-release hard capsules prolonged-release capsules,

hard should not be used in children under 12 years of age.

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 Zamadol SR prolonged-release hard capsules

Tell your doctor or pharmacist or dentist if you are taking, have recently

taken or might take any other medicines, including those obtained

without prescription.

Do not take Zamadol SR prolonged-release hard capsules at the same time,

or within 14 days of taking medicines called monoamine oxidase inhibitors

(moclobemide or phenelzine for depression, selegiline for Parkinson’s

disease).

The pain relieving effect of Zamadol SR prolonged-release hard capsules

may be weakened and/or shortened if you also take medicines

containing:

- carbamazepine (used to treat epilepsy)

- buprenorphine, nalbuphine, or pentazocine (pain killers)

- ondansetron (prevents nausea)

Your doctor will tell you whether you should take Zamadol SR

prolonged-release hard capsules and what 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 of having a fit may increase if you take Zamadol SR

prolonged-release hard capsules at the same time. Your doctor will tell you

whether Zamadol SR prolonged-release hard capsules are suitable for you.

The risk of side effect increases, if you are taking certain antidepressants.

Zamadol SR prolonged-release hard capsules 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.

Medicines that act on the nervous system such as hypnotics, tranquillisers,

sleeping pills and pain killers may make you feel drowsier or faint

when taken with Zamadol SR prolonged-release hard capsules.

Anticoagulants to thin your blood such as warfarin. The effectiveness of the

medicines may be altered if you are also taking Zamadol SR

prolonged-release hard capsules.

You must tell your doctor if you are taking these medicines.

Concomitant use of Zamadol SR prolonged-release hard capsules 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 Zamadol SR prolonged-release hard

capsules 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.

Zamadol SR prolonged-release hard capsules with food, drink and

alcohol

Zamadol SR prolonged-release hard capsules should be taken with some

water, with or without the meal. Avoid drinking alcohol while taking this

medicine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are

planning to have a baby, ask your doctor or pharmacist for advice

before taking this medicine. Please contact your doctor if you become

pregnant during your treatment.

Pregnancy

Zamadol SR prolonged-release hard capsules should not be taken during

pregnancy or while breast-feeding. This is because it is not yet known how

safe it is to take this medicine when you are pregnant. Contact your doctor if

you become pregnant during your treatment.

Breast-feeding

Tramadol is excreted into breast milk. For this reason, you should not take

Zamadol SR prolonged-release hard capsules more than once during

breast-feeding, or alternatively, if you take Zamadol SR prolonged-release

hard capsules more than once, you should stop breast-feeding.

Driving and using machines

Zamadol SR prolonged-release hard capsules may cause drowsiness and

this effect may be potentiated by alcohol, anti-histamines and other CNS

depressants. If patients are affected they should be warned not to drive or

operate machinery.

Zamadol SR prolonged-release hard capsules contains sucrose.

If you have been told by your doctor that you have intolerance to some

sugars, contact your doctor before taking this medicinal product.

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(tramadol hydrochloride)

Patient Information Leaflet (continued)

How to take Zamadol SR prolonged-release

hard capsules

Always take this medicine exactly as your doctor has told you. Check with

your doctor or pharmacist if you are not sure.

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

individual pain sensitivity. In general the lowest pain-relieving dose

should be taken.

Swallow the capsules whole with water without chewing.

If you have difficulty in swallowing, you may open the capsules. You must

open them very carefully by pulling and twisting each end over a

spoon so that all the pellets stay in the spoon. Do not chew. Swallow all the

pellets with water.

Dosage for adults and adolescents from 12 years of age:

The usual initial dose is 50–100 mg twice daily, in the morning and in the

evening. Your doctor may increase this dose up to 150–200 mg twice daily

according to your needs. You should normally take your Zamadol SR

prolonged-release hard capsules every 12 hours, at the same time each

morning and evening.

The maximum dose is usually 400 mg daily.

Dosage for

Use in children:

Under 12 years of age – Zamadol SR prolonged-release hard capsules

should not be taken by children under 12 years of age.

Use in elderly patients:

In elderly patients (above 75 years of age) the excretion of tramadol may be

delayed. If this applies to you, your doctor may recommend

prolonging the dosage interval.

Use in patients with severe liver or kidney disease (insufficiency)/

dialysis patients:

Patients with severe liver and/or kidney insufficiency should not take

Zamadol SR prolonged-release hard capsules. If in your case the

problem is mild or moderate your doctor may recommend prolonging the

dosage interval.

If you take more Zamadol SR prolonged-release hard capsules than

you should

If you accidentally take more capsules than your prescribed dose, tell your

doctor or pharmacist immediately and if necessary contact your

nearest hospital casualty department. Remember to take the pack and any

remaining medicines with you.

If you forget to take Zamadol SR prolonged-release hard capsules

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

If you stop taking Zamadol SR prolonged-release hard capsules

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).

People who have been taking Zamadol SR prolonged-release capsules,

hard for some time may feel unwell if they abruptly stop taking them.

They may feel agitated, anxious, nervous or shaky. They may be

hyperactive, have difficulty sleeping and have stomach or bowel disorders.

If you experience any of these complaints after stopping Zamadol SR

prolonged-release capsules, hard please consult your doctor.

If you have any further questions on the use of this medicine, ask your

doctor or pharmacist.

Possible side effects

Like all medicines, Zamadol SR prolonged-release hard capsules can cause

side effects, although not everybody gets them.

The most serious side effects which may occur include allergic reaction

(difficulty in breathing, wheezing and swelling of the face or throat),

anaphylactic reaction (an extreme allergic reaction resulting in difficulty

breathing, changes in heart rate, faintness, collapse or unconsciousness

due to a drop in blood pressure) or convulsions (fits). If you have any of

these symptoms you must stop taking Zamadol SR prolongedrelease

hard capsules immediately and seek medical advice.

Very common (may affect more than 1 in 10 people)

*

Dizziness

*

Vomiting and nausea (being and feeling sick)

Common (may affect up to 1 in 10 people)

*

Headache

*

Drowsiness, sleepiness (fatigue)

*

Constipation, dry mouth

*

Sweating

Uncommon (may affect up to 1 in 100 people)

*

Rapid heartbeat, palpitation, sudden drops in blood pressure. These

adverse effects may occur especially on intravenous administration

and in patients who are physically stressed

*

Itching, skin rash

*

Retching, feeling bloated or full

Rare (may affect up to 1 in 1,000 people)

*

Appetite changes

*

Psychic effects including: changes in mood, activity behaviour and

perception, hallucinations, confusion, restlessness sleep disturbances

and nightmares

*

Convulsions (fits)

*

Tingling sensation and trembling

*

Slow heart-beat, increase in blood pressure

*

Muscle weakness

*

Difficulty or inability in passing urine

*

Blurred vision

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

*

Flushing

*

Vertigo (feeling of dizziness or “spinning”)

*

Asthma and breathing difficulties

*

Elevated liver enzymes

Not known: frequency cannot be estimated from the available data

*

Decrease in blood sugar level

Withdrawal symptoms including: agitation, anxiety, nervousness, difficulty

sleeping, restlessness, trembling and gastro-intestinal problems

(see section 3. How to take Zamadol SR prolonged-release hard capsules).

Reporting of side effects

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

any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at:

ww.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the

Google Play or Apple App Store.

By reporting side effects you can help provide more information on the

safety of this medicine.

How to store Zamadol SR prolonged-release hard

capsules

*

KEEP OUT OF THE SIGHT AND REACH OF CHILDREN

*

Store in the original package in order to protect from moisture.

*

Do not store above 25 °C.

*

Do not take this medicine after the expiry date which is printed on the

blister or carton label. If your doctor tells you to stop taking the medicine,

take any remaining medicine back to the pharmacist for safe disposal.

Only keep this medicine if your doctor tells you to.

*

If your medicine becomes discoloured or shows any other signs of

deterioration, ask your pharmacist who will advise you what to do.

*

Medicines should not be disposed of via waste water or household waste.

Ask your pharmacist how to dispose of medicines no longer required.

These measures will help to protect the environment.

Contents of the pack and other information

What Zamadol SR prolonged-release hard capsules contains:

The active substance is tramadol hydrochloride.

Each capsules contains 200mg of tramadol hydrochloride.

The other ingredients of the capsule contents are: sugar spheres (sucrose

and maize starch), colloidal anhydrous silica, ethylcellulose, shellac and talc.

The capsule contains: gelatin, titanium dioxide (E171) and iron oxide yellow

(E172).

The printing ink contains: shellac, iron oxide black (E172), propylene glycol

and ammonium hydroxide.

What Zamadol SR prolonged-release hard capsules looks like and

contents of the pack

Zamadol SR 200mg prolonged-release hard capsules are yellow marked

with T200SR in black ink.

Each pack contains 60 prolonged-release hard capsules.

Manufacturer and Licence Holder

This medicine is manufactured by Temmler Pharma GmbH, Marburg, Germany

and is procured from within the EU and repackaged by the Product Licence

Holder: Lexon (UK) Limited, Unit 18, Oxleasow Road, East Moons Moat,

Redditch, Worcestershire, B98 0RE.

If you have any questions or are not sure about anything, ask your doctor or

pharmacist. They will have additional information about this medicine and

will be able to advise you.

PL 15184/1384

Zamadol SR 200mg prolonged-release

hard capsules

Zamadol is a registered trademark of MEDA Pharma GmbH & Co. KG.

Revision date: 16/07/19

Blind or partially sighted?

Is this leaflet hard to see or read?

Phone Lexon (UK) Limited,

Tel: 01527 505414 to obtain the leaflet

in a format suitable for you

POM

Ref: 1384/160719/1/B

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Zamadol SR 200mg prolonged-release hard capsules

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3

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Zamadol SR 200 mg prolonged-release hard capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 200mg of tramadol hydrochloride

Excipients with known effect

This product contains sucrose (37.5 mg/capsule).

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Prolonged release hard capsule

The 200 mg capsules are yellow of about 19 – 19.5 mm, marked T200SR

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of 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.

Dosage for adults and adolescents from 12 years of age:

The usual initial dose is 50-100 mg twice daily, in the morning and in the evening.

This dose may be titrated up to 150-200 mg twice daily according to pain severity.

If long-term pain treatment with tramadol hydrochloride is necessary in view of the

nature and severity of the illness, then careful and regular monitoring should be

carried out (if necessary with breaks in treatment) to establish whether and to what

extent further treatment is necessary.

A total oral daily dose of 400 mg should not be exceeded except in special clinical

circumstances.

Paediatric population:

Zamadol SR prolonged-release hard capsules should not be used in children under 12

years of age since safety and efficacy have not been established.

Elderly patients:

A dose adjustment is usually not necessary in patients up to 75 years of age without

clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years of

age 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 Zamadol SR

prolonged-release capsules is delayed. In these patients prolongation of the dosage

intervals should be carefully considered according to the patient’s requirements.

Zamadol SR capsules are not recommended for patients with severe hepatic and/or

renal insufficiency.

Method of administration

The capsules are intended for twice daily oral administration and can be taken

independently of meal times, swallowed whole with water.

Patients who have swallowing problems:

Zamadol SR prolonged-release hard capsules can be opened, carefully, so that the

pellets are deposited on a spoon. The spoon and pellets should be taken into the

mouth, followed by a drink of water to rinse the mouth of all pellets. The pellets must

not be chewed or crushed.

4.3

Contraindications

With hypersensitivity to the active substance tramadol hydrochloride or to

any of the excipients listed in section 6.1.

With acute intoxication with hypnotics, centrally acting analgesics, opioids,

psychotropic drugs or alcohol.

If monoamine oxidase inhibitors (specific drugs acting against depression)

are taken concomitantly or have been taken within the last 14 days before

treatment with Zamadol SR prolonged-release hard capsules

Who are suffering from uncontrolled epilepsy.

Tramadol must not be used for narcotic withdrawal treatment.

4.4

Special warnings and precautions for use

Risk from concomitant use of sedative medicines such as benzodiazepines or related

drugs:

Concomitant use of Zamadol SR prolonged-release hard capsules and sedative

medicines such as benzodiazepines or related drugs may result in sedation, respiratory

depression, coma and death. Because of these risks, concomitant prescribing with

these sedative medicines should be reserved for patients for whom alternative

treatment options are not possible. If a decision is made to prescribe Zamadol SR

prolonged-release hard capsules concomitantly with sedative medicines, 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).

Risk of tolerance, dependence and withdrawal symptoms:

Tolerance, psychic and physical dependence may develop, especially after long-term

use. When a patient no longer requires therapy with tramadol, it may be advisable to

taper the dose gradually to prevent symptoms of withdrawal. In patients with a

tendency to drug abuse or dependence, treatment should be for short periods under

strict medical supervision. In rare cases at therapeutic doses, tramadol has the

potential to cause withdrawal symptoms.

Zamadol SR prolonged-release hard capsules are not a suitable substitute in opioid

dependent patients. The product does not suppress morphine withdrawal symptoms

although it is an opioid agonist.

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%

Convulsions have been reported at therapeutic doses and the risk may be increased at

doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or

those susceptible to seizures should only be treated with tramadol if there are

compelling reasons. The risk of convulsions may increase in patients taking tramadol

and concomitant medication that can lower the seizure threshold (see section 4.5)

Zamadol SR prolonged-release hard capsules should be used with prudence in

patients who have shown previous hypersensitivity to opiates, and in patients with

severe renal or hepatic impairment, head injury, decreased level of consciousness,

increased intracranial pressure, or patients in shock or at risk of convulsions.

At recommended therapeutic doses Zamadol SR prolonged-release hard capsules are

unlikely to produce clinically relevant respiratory depression. Care should however be

taken when administering Zamadol SR prolonged-release hard capsules to patients

with existing respiratory depression or excessive bronchial secretion and in those

patients taking concomitant CNS depressant drugs.

Paediatric population

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

apnea, 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.

This medicinal product contains sucrose and therefore should not be used by patients

with rare hereditary problems of fructose intolerance, glucose-galactose

malabsorption or sucrase-isomaltase insufficiency.

4.5

Interaction with other medicinal products and other forms of interaction

Patients treated with monoamine oxidase inhibitors within 14 days prior to the

administration of the opioid pethidine have experienced life-threatening interactions

affecting the central nervous system as well as the respiratory and circulatory centres.

The possibility of similar interactions occurring between monoamine oxidase

inhibitors and tramadol cannot be ruled out.

Tramadol may potentiate the CNS depressant effects of other centrally acting drugs

(including alcohol) when administered concomitantly with such drugs.

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).

Tramadol can induce convulsions and increase the potential for selective serotonin

reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs),

tricyclic antidepressants (TCAs), antipsychotics and other seizure threshold-lowering

drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions

(see section 4.4)

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 or 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.

Administration of Zamadol SR prolonged-release hard capsules together with

carbamazepine results in markedly decreased serum concentrations of tramadol which

may reduce analgesic effectiveness and shorten the duration of action.

Caution should be exercised during concomitant treatment with tramadol and

coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses

in some patients.

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine,

pentazocine) and tramadol is not recommended because it is theoretically possible

that the analgesic effect of a pure agonist is attenuated under these circumstances.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of

norepinephrine and enhancement of the release of serotonin (5-HT). In studies the

pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron

increased the requirements of tramadol in patients with postoperative pain.

There is no interaction with food.

4.6

Fertility, pregnancy and lactation

Pregnancy:

Zamadol SR prolonged-release hard capsules should not be used during pregnancy as

there is inadequate evidence available to assess the safety of tramadol in pregnant

women. Tramadol - administered before or during birth - does not affect uterine

contractility. In neonates it may induce changes in the respiratory rate which are

usually not clinically relevant.

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

Animal studies did not show an effect of tramadol on fertility, reproductive

performance and development of offspring.

4.7

Effects on ability to drive and use machines

Zamadol SR prolonged-release hard capsules may cause drowsiness and this effect

may be potentiated by alcohol, anti-histamines and other CNS depressants. If patients

are affected they should be warned not to drive or operate machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive

safely. This class of medicine is in the list of drugs included in regulations under 5a of

the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’)

The medicine has been prescribed to treat a medical or dental problem and

You have taken it according to the instructions given by the prescriber and in

the information provided with the medicine and

It was not affecting your ability to drive safely

4.8

Undesirable effects

The most commonly reported adverse drug reactions are nausea and dizziness, both

occurring in more than 10% of patients.

Immune system disorders:

Rare (

1/10,000 to < 1/1,000): Allergic reactions (e.g. dyspnoea, bronchospasm,

wheezing, angioneurotic oedema) and anaphylaxis.

Metabolism and nutrition disorders:

Rare (

1/10,000 to < 1/1,000): Changes in appetite.

Frequency not known (cannot be estimated from the available data): Hypoglycaemia

Psychiatric disorders:

Rare (

1/10,000 to < 1/1,000): psychic side-effects may occur following

administration of tramadol which vary individually in intensity and nature (depending

on personality and duration of medication). These include changes in mood (usually

elation, occasionally dysphoria), changes in activity (usually suppression,

occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision

behaviour, perception disorders), hallucinations, confusion, sleep disturbances and

nightmares.

Prolonged administration of Zamadol SR prolonged-release hard capsules may lead to

dependence (see section 4.4) Symptoms of withdrawal reactions, similar to those

occurring during opiate withdrawal, may occur as follows: agitation, anxiety,

nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Nervous system disorders:

Very common (

1/10) dizziness.

Common (

1/100 to < 1/10): headache, drowsiness.

Rare (

1/10,000 to < 1/1,000): epileptiform convulsions occurred mainly after

administration of high doses of tramadol or after concomitant treatment with drugs

which can lower the seizure threshold or themselves induce cerebral convulsions (e.g.

antidepressants or anti-psychotics, see section 4.5 "Interaction with other medicinal

products and other forms of interaction".

Paraesthesia and tremor.

Very rare (< 1/10,000): vertigo

Eye disorders:

Rare (

1/10,000 to < 1/1,000): blurred vision.

Cardiac disorders:

Uncommon (

1/1,000 to < 1/100): effects on cardiovascular regulation (palpitation,

tachycardia, postural hypotension or cardiovascular collapse). These adverse effects

may occur especially on intravenous administration and in patients who are physically

stressed.

Rare (

1/10,000 to < 1/1,000): bradycardia, increase in blood pressure.

Vascular disorders:

Very rare (< 1/10,000): flushing.

Gastrointestinal disorders:

Very common (

1/10): vomiting, nausea.

Common (

1/100 to < 1/10): constipation, dry mouth.

Uncommon (

1/1,000 to < 1/100): retching, gastrointestinal irritation (a feeling of

pressure in the stomach, bloating).

Hepatobiliary disorders:

In a few isolated cases an increase in liver enzyme values has been reported in a

temporal connection with the therapeutic use of tramadol.

Skin and subcutaneous tissue disorders:

Common (

1/100 to < 1/10): sweating.

Uncommon (

1/1,000 to < 1/100): dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders:

Rare (

1/10,000 to < 1/1,000): motorial weakness.

Renal and urinary system disorders:

Rare (

1/10,000 to < 1/1,000): micturition disorders (difficulty in passing urine and

urinary retention).

General disorders and administration site conditions:

Common (

1/100 to < 1/10): fatigue.

Worsening of asthma has also been reported, though a causal relationship has not

been established.

Respiratory depression has been reported. If the recommended doses are considerably

exceeded and other centrally depressant substances are administered concomitantly

(see section 4.5 "Interaction with other medicinal products and other forms of

interaction") respiratory depression may occur.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA

Yellow Card in the Google Play or Apple App Store.

4.9

Overdose

Symptoms of tramadol overdose include vomiting, miosis, sedation, seizures,

respiratory depression and hypotension, with circulatory failure and coma.

Respiratory failure may also occur. Such symptoms are typical of opioid

analgesics.

Treatment of overdose requires the maintenance of the airway and

cardiovascular functions. Respiratory depression may be reversed using

naloxone and fits controlled with diazepam. Naloxone administration may

increase the risk of seizures.

The treatment of acute overdose of tramadol using haemodialysis or

haemofiltration alone is not sufficient or suitable due to the slow elimination

of tramadol from the serum by these routes.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Other opioids, ATC code: N02AX02

Tramadol is a centrally acting analgesic which possesses opioid agonist

properties. Tramadol consists of two enantiomers, the (+)-isomer is

predominantly active as an opioid with preferential activity for the

-receptor.

The (-)-isomer potentiates the analgesic effect of the (+)-isomer and is active

as an inhibitor of noradrenaline and serotonin-uptake thereby modifying the

transmission of pain impulses.

Tramadol also has an antitussive action. At the recommended dosages, the effects of

tramadol given orally on the respiratory and cardiovascular systems appear to be

clinically insignificant. The potency of tramadol is reported to be 1/10 to 1/6 of

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 2mg/kg or multiple doses of up to 8mg/kg per day (to a

maximum of 400mg 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 that 1 year (see

section 4.2).

5.2

Pharmacokinetic properties

Absorption

About 90% of tramadol released from Zamadol SR prolonged-release hard capsules is

absorbed after oral administration. The mean absolute bioavailability is approximately

70%, irrespective of concomitant intake of food.

The difference between absorbed and non-metabolised available tramadol is probably

due to low first-pass effect. The first pass-effect after oral administration is a

maximum of 30%.

Tramadol has a high tissue affinity with an apparent volume of distribution of 203 ±

40 litres after oral dosing in healthy volunteers. Protein binding is limited to 20%.

After single dose administration of Zamadol SR 50 mg prolonged-release hard

capsules the peak plasma concentration C

70 ± 16 ng/ml is reached after 5.3 h.

After administration of Zamadol SR 100 mg prolonged-release hard capsules C

137 ± 27 ng/ml is reached after 5.9 h. Following administration of Zamadol SR 200

mg prolonged-release hard capsules C

294 ± 82 ng/ml is reached after 6.5 h. The

reference product (Tramadol Immediate Release Capsules, given as a total dose of

200 mg tramadol hydrochloride) reached a peak concentration of C

640 ± 143

ng/ml after 2.0 hours.

The relative bioavailability for the slow release formulation after single dose

administration is 89% and increases to 100% after multiple dose administration in

comparison to the reference product.

Tramadol passes the blood-brain and placenta barriers. Very small amounts of the

substance and its O-demethyl derivative are found in the breast-milk (0.1% and

0.02% respectively of the applied dose).

Biotransformation

In humans tramadol is mainly metabolised by means of N- and O-demethylation and

conjugation of the O-demethylation products with glucuronic acid. Only O-

desmethyltramadol is pharmacologically active. There are considerable

interindividual quantitative differences between the other metabolites. So far, eleven

metabolites have been found in the urine. Animal experiments have shown that O-

desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half

life t

(6 healthy volunteers) is 7.9 h (range 5.4-9.6 h) and is approximately that of

tramadol.

The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6

involved in the biotransformation of tramadol may affect the plasma concentration of

tramadol or its active metabolite.

Elimination

Elimination of half-life t

is approximately 6 h, irrespective of the mode of

administration. In patients above 75 years of age it may be prolonged by a factor of

1.4.

Tramadol and its metabolites are almost completely excreted via the kidneys.

Cumulative urinary excretion is 90% of the total radioactivity of the administered

dose. In cases of impaired hepatic and renal function the half-life may be slightly

prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h

(tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36

h respectively have been determined. In patients with renal insufficiency (creatinine

clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case

19.5 h and 43.2 h, respectively.

Linearity

Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

Pharmacokinetic/pharmacodynamic relationship

The relationship between serum concentrations and the analgesic effect is dose-

dependent, but varies considerably in isolated cases. A serum concentration of 100 -

300 ng/ml is usually 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

Pre-clinical data reveal no special hazard for humans based on conventional studies of

safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Studies of tramadol in rats and rabbits have revealed no teratogenic effects. However,

embryo toxicity was shown in the form of delayed ossification. Fertility, reproductive

performance and development of offspring were unaffected.

6

PHARMACEUTICAL PARTICULARS

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