Tramadol 50mg capsules

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Tramadol hydrochloride
Available from:
NorthStar Healthcare Unlimited Company
ATC code:
N02AX02
INN (International Name):
Tramadol hydrochloride
Dosage:
50mg
Pharmaceutical form:
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: 05051089990657 05051089990664

350x210 Leaflet Reel Fed Profile Landscape (BST)

Dimensions:

Component:

Date Sent:

Technologist:

Technically Approved

Pharmacode:

JDE No.:

Tramadol Hydrochloride Capsules

50mg x 30, 100 (UK)

350x210 (Reel Fed)

50988803

Leaflet for Blisters

3737

T. Hull

28/02/20

* Please note that only Artwork Studio is permitted to make changes to the above artwork.

No changes are permitted by any 3rd party other than added notes and mark ups for required changes.

approved for print/date

Proof Round

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Approval

Non Printing Colours

Colours

Date sent:

Date received:

Item number:

Originator:

Origination Date:

Revision Date:

Revised By:

Dimensions:

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Supplier:

EU-Artwork-Support@accord-healthcare.com

Tramadol 50mg Capsules Blister pack PIL - UK

Black

Profile

BBBA7635

02/03/2020

22/04/2020

350 x 210 (Reel Fed)

9 pts

Accord Barnstaple

05

Version 7

12.02.2020

German GTIN 14

(incorporating PZN):

NA

Cartons and label leaflets only

(labels only when specified)

page 1

page 4

50988803 BBBA7635

This medicine contains Tramadol hydrochloride

which is an opioid, which can cause addiction. You

can get withdrawal symptoms if you stop taking it

suddenly.

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 the leaflet. See section 4.

What is in this leaflet

1

What Tramadol capsules are and what they

are used for

2

What you need to know before you take

Tramadol capsules

3

How to take Tramadol capsules

4

Possible side effects

5

How to store Tramadol capsules

6

Contents of the pack and other information

1

What Tramadol capsules are and what they

are used for

This medicine has been prescribed for you for the relief of

moderate or severe pain.

It contains Tramadol hydrochloride which belongs to a

class of medicines called opioids, which are ‘pain relievers’.

This medicine has been prescribed to you and should not

be given to anyone else.

Opioids can cause addiction and you may get withdrawal

symptoms if you stop taking it suddenly. Your prescriber

should have explained how long you will be taking it for

and when it is appropriate to stop, how to do this safely.

2

What you need to know before you take

Tramadol capsules

Do not take Tramadol capsules:

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

ingredients of this medicine (listed in section 6).

in acute poisoning with alcohol, sleeping pills, pain

relievers or other psychotropic medicines (medicines

that affect mood and emotions).

if you are also taking MAO inhibitors (certain medicines

used for treatment of depression) or have taken them in

the last 14 days before treatment with Tramadol capsules

(see “Other medicines and Tramadol capsules”).

if you are an epileptic and your fits are not adequately

controlled by treatment.

as a substitute in drug withdrawal.

if you are breast-feeding.

Warnings and precautions:

Talk to your doctor or pharmacist before taking

Tramadol capsules if you:

suffer from consciousness disorders (if you feel that you

are going to faint);

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

suffer from increased pressure in the brain (possibly after

a head injury or brain disease);

have difficulty in breathing;

have a tendency towards epilepsy or fits because the risk

of a fit may increase;

suffer from a liver or kidney disease;

are or have ever been addicted to opioids, alcohol,

prescription medicines, or illegal drugs.

have previously suffered from withdrawal symptoms

such as agitation, anxiety, shaking or sweating, when you

have stopped taking alcohol or drugs.

feel you need to take more Tramadol capsules to get

the same level of pain relief, this may mean you are

becoming tolerant to the effects of this medicine or are

becoming addicted to it. Speak to your prescriber who

will discuss your treatment and may change your dose

or switch you to an alternative pain reliever.

Taking this medicine regularly, particularly for a long

time, can lead to addiction. Your prescriber should have

explained how long you will be taking it for and when it is

appropriate to stop, how to do this safely.

Rarely, increasing the dose of this medicine can make you

more sensitive to pain. If this happens, you need to speak

to your prescriber about your treatment.

Uncommon (may affect up to 1 in 100 people):

effects on the heart and blood circulation (pounding of the

heart, fast heartbeat, feeling faint or collapse). These adverse

effects may particularly occur in patients in an upright

position or under physical strain.

urge to be sick (retching), stomach trouble (e.g. feeling of

pressure in the stomach, bloating), diarrhoea

skin reactions (e.g. itching, rash)

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

allergic reactions (e.g. difficulty in breathing, wheezing,

swelling of skin) and shock (sudden circulation failure) have

occurred in very rare cases.

slow heartbeat

increase in blood pressure

abnormal sensations (e.g. pins and needles), trembling,

epileptic fits, muscle twitches, uncoordinated movement,

transient loss of consciousness (syncope), speech disorders.

Epileptic fits have occurred mainly at high doses of tramadol

or when tramadol was taken at the same time as other

medicines which may induce fits.

changes in appetite

hallucination, confusional state, sleep disorders, delirium,

anxiety and nightmares

psychological complaints may appear after treatment with

Tramadol. Their intensity 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 (usually

suppression, occasionally increase) and decreased cognitive

and sensory perception (being less aware and less able to

make decisions, which may lead to errors in judgement).

blurred vision, excessive dilation of the pupils (mydriasis),

constriction of the pupil (miosis).

slow breathing, shortness of breath (dyspnoea)

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.

weak muscles

passing urine with difficulty or pain, passing less urine than

normal (dysuria).

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

liver enzymes increased

Not known (frequency cannot be estimated from the

available data):

decrease in blood sugar level

dependence and addiction (see section “How do I know if I

am addicted?”).

Drug Withdrawal

When you stop taking Tramadol capsules, you may experience

drug withdrawal symptoms, which include restlessness,

difficulty sleeping, irritability, agitation, anxiety, feeling your

heartbeat (palpitations), increased blood pressure, feeling or

being sick, diarrhoea, shaking, shivering or sweating.

How do I know if I am addicted?

If you notice any of the following signs whilst taking Tramadol

capsules, it could be a sign that you have become addicted.

You need to take the medicine for longer than advised by

your prescriber

You feel you need to use more than the recommended dose

You are using the medicine for reasons other than

prescribed

When you stop taking the medicine you feel unwell, and you

feel better once taking the medicine again

If you notice any of these signs, it is important you talk to your

prescriber

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 the Yellow

Card Scheme at: www.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.

5

How to store Tramadol capsules

Keep out of the sight and reach of children.

Do not store above 30°C.

Do not take Tramadol capsules after the expiry date stated on

the label/carton/bottle. The expiry date refers to the last day of

that month.

Do not throw away this medicine via wastewater or

household waste. Ask your pharmacist how to dispose of

medicines you no longer use. These measures will help to

protect the environment.

6

Contents of the pack and other information

What Tramadol capsules contain

The active substance is tramadol hydrochloride.

The other ingredients are pregelatinised starch,

microcrystalline cellulose (E460), magnesium stearate

The capsule shell contains gelatin, iron oxide (E172), titanium

dioxide (E171), indigo carmine (E132). The printing ink

contains shellac glaze, iron oxide black (E172) and propylene

glycol.

What Tramadol capsules look like and contents of

the pack

Tramadol capsules are yellow and green, opaque, hard gelatin

capsules printed “TK” in black.

Pack sizes are 30 and 100.

Marketing Authorisation Holder and Manufacturer

Accord, Barnstaple, EX32 8NS, UK

Date of revision: April 2020

Package leaflet: Information for the patient

Tramadol hydrochloride

50mg capsules

350x210 Leaflet Reel Fed Profile Landscape (BST)

Dimensions:

Component:

Date Sent:

Technologist:

Technically Approved

Pharmacode:

JDE No.:

Tramadol Hydrochloride Capsules

50mg x 30, 100 (UK)

350x210 (Reel Fed)

50988803

Leaflet for Blisters

3737

T. Hull

28/02/20

* Please note that only Artwork Studio is permitted to make changes to the above artwork.

No changes are permitted by any 3rd party other than added notes and mark ups for required changes.

approved for print/date

Proof Round

Technical

Approval

Non Printing Colours

Colours

Date sent:

Date received:

Item number:

Originator:

Origination Date:

Revision Date:

Revised By:

Dimensions:

Min Body Text Size:

Supplier:

EU-Artwork-Support@accord-healthcare.com

Tramadol 50mg Capsules Blister pack PIL - UK

Black

Profile

BBBA7635

02/03/2020

22/04/2020

350 x 210 (Reel Fed)

9 pts

Accord Barnstaple

05

Version 7

12.02.2020

German GTIN 14

(incorporating PZN):

NA

Cartons and label leaflets only

(labels only when specified)

page 2

page 3

Addiction can cause withdrawal symptoms when you stop taking

this medicine. Withdrawal symptoms can include restlessness,

difficulty sleeping, irritability, agitation, anxiety, feeling your

heartbeat (palpitations), increased blood pressure, feeling or being

sick, diarrhoea, loss of appetite, shaking, shivering or sweating.

Your prescriber will discuss with you how to gradually reduce your

dose before stopping the medicine. It is important that you do not

stop taking the medicine suddenly as you will be more likely to

experience withdrawal symptoms.

Opioids should only be used by those they are prescribed for. Do

not give your medicine to anyone else. Taking higher doses or

more frequent doses of opioid, may increase the risk of addiction.

Overuse and misuse can lead to overdose and/or death.

Sleep-related breathing disorders

Tramadol capsules contain an active substance that belongs to

the group of opioids. Opioids can cause sleep-related breathing

disorders, for example central sleep apnea (shallow/pause of

breathing during sleep) and sleep-related hypoxemia (low level of

oxygen in the blood).

The risk of experiencing central sleep apnea is dependent on the

dose of opioids. Your doctor may consider decreasing your total

opioid dosage if you experience central sleep apnea.

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).

Please also inform your doctor if one of these problems occurs

during Tramadol treatment or if they applied to you in the past.

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.

Other medicines and Tramadol capsules

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

or might take any other medicines.

Tramadol capsules should not be taken together with MAO

inhibitors (certain medicines for the treatment of depression).

The pain-relieving effect of Tramadol may be reduced and the

length of time it acts may be shortened, if you take medicines

which contain

carbamazepine (for epileptic fits);

ondansetron (prevents nausea).

Your doctor will tell you whether you should take Tramadol

capsules, and which dose.

The risk of side effects increases,

if you are taking other pain relievers such as morphine and

codeine (also as cough medicine), and alcohol while you are

taking Tramadol capsules. You may feel drowsier or feel that you

might faint. If this happens tell your doctor.

Concomitant use of Tramadol capsules and tranquillizers

or sleeping pills (e.g. benzodiazepines), 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 prescribes Tramadol

capsules together with sedating medicines the dose and the

duration of concomitant treatment should be limited by your

doctor. Please tell your doctor about all sedating 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

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 Tramadol capsules at the

same time. Your doctor will tell you whether Tramadol capsules

are suitable for you.

if you are taking certain antidepressants, Tramadol 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 .

if you are taking coumarin anticoagulants (medicines for blood

thinning), e.g. warfarin, together with Tramadol capsules. The

effect of these medicines on blood clotting may be affected and

bleeding may occur.

Tramadol capsules with food and alcohol

Do not drink alcohol during treatment with Tramadol capsules as

the effect may be intensified.

Food does not influence the effect of Tramadol capsules.

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.

Pregnancy, breast-feeding and fertility

Do not take Tramadol capsules if you are pregnant or think

you might be pregnant unless you have discussed this with

your prescriber and the benefits of treatment are considered to

outweigh the potential harm to the baby.

If you use Tramadol capsules during pregnancy, your baby may

become dependent and experience withdrawal symptoms after

the birth which may need to be treated.

Do not take Tramadol capsules while you are breastfeeding as

Tramadol passes into breast milk and will affect your baby.

Based on human experience, tramadol is suggested not to

influence female or male fertility.

Driving and using machines

Tramadol capsules may make you feel drowsy, dizzy or in rare

cases blur your vision. This may be made worse if you drink alcohol

or take other medicines such as strong painkillers with tramadol.

Make sure you are not affected before you drive or operate

machinery.

The medicine can affect your ability to drive as it may make you

sleepy or dizzy.

Do not drive while taking this medicine until you know how it

affects you.

It is an offence to drive if this medicine affects your ability to drive.

However, you would not be committing an offence if:

- 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 or in the information provided with the medicine

- It was not affecting your ability to drive safely

Talk to your doctor or pharmacist if you are not sure whether it is

safe for you to drive while taking this medicine.

3

How to take Tramadol capsules

Always take this medicine exactly as your doctor or pharmacist 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. Do not take more than 400 mg tramadol

hydrochloride daily, except if your doctor has instructed you to do

Unless otherwise prescribed by your doctor, the usual dose is:

Adults and adolescents from the age of 12 years

One or two Tramadol capsules (equivalent to 50 mg – 100 mg

tramadol hydrochloride)

Depending on the pain the effect lasts for about 4-8 hours.

Your doctor may prescribe a different, more appropriate dosage of

Tramadol if necessary.

Children

Tramadol 50 mg Capsules are not suitable for children below the

age of 12 years.

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 insufficiency should not

take Tramadol capsules. If in your case the insufficiency is mild or

moderate, your doctor may recommend prolonging the dosage

interval.

How and when should you take Tramadol capsules?

Tramadol capsules are for oral use.

Always swallow Tramadol capsules whole, not divided or chewed,

with sufficient liquid, preferably in the morning and evening. You

may take the capsule on an empty stomach or with meals.

How long should you take Tramadol Capsules

Your prescriber should have discussed with you, how long the

course of Tramadol capsules will last. They will arrange a plan for

stopping treatment. This will outline how to gradually reduce the

dose and stop taking the medicine.

You should not take Tramadol Capsules 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 Tramadol Capsules and at

what dose.

If you have the impression that the effect of Tramadol Capsules is

too strong or too weak, talk to your doctor or pharmacist.

If you take more Tramadol Capsules than you should

If you have taken an additional dose by mistake, this will generally

have no negative effects. You should take your next dose as

prescribed.

If you (or someone else) swallow a lot of Tramadol capsules at the

same time, you should go to hospital or call a doctor straight away.

Signs of an overdose include very small pupils, being sick, fall in

blood pressure, fast heartbeat, collapse, unconsciousness, fits and

breathing difficulties or shallow breathing.

If you forget to take Tramadol Capsules

If you forget to take the capsule, pain is likely to return. Do not take

a double dose to make up for forgotten individual doses, simply

continue taking the capsule as before.

If you stop taking Tramadol Capsules

If you interrupt or finish treatment with Tramadol too soon, pain

is likely to return. If you wish to stop treatment on account of

unpleasant effects, please tell your doctor.

Do not suddenly stop taking this medicine. If you want to stop

taking this medicine, discuss this with your prescriber first. They

will tell you how to do this, usually by reducing the dose gradually

so that any unpleasant withdrawal effects are kept to a minimum.

Withdrawal symptoms such as restlessness, difficulty sleeping,

irritability, agitation, anxiety, feeling your heartbeat (palpitations),

increased blood pressure, feeling or being sick, diarrhoea, shaking,

shivering or sweating may occur if you suddenly stop taking this

medicine. Very few people may get panic attacks, hallucinations,

unusual perceptions such as itching, tingling and numbness, and

“ringing” in the ears (tinnitus). Further unusual central nervous

system symptoms, i.e. confusion, delusions, change of perception

of the own personality (depersonalisation), and change in

perception of reality (derealisation) and delusion of persecution

(paranoia) have been seen very rarely. If you experience any of

these complaints after stopping Tramadol, please consult your

doctor.

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

your doctor or pharmacist.

4

Possible side effects

Like all medicines, this medicine can cause side effects, although

not everybody gets them.

You should see a doctor immediately if you experience

symptoms of an allergic reaction such as swollen face, tongue

and/or throat, and/or difficulty swallowing or hives together

with difficulties in breathing.

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

dizziness, feeling sick (nausea)

Common (may affect up to 1 in 10 people):

headaches, drowsiness, fatigue, constipation, dry mouth, being

sick (vomiting), sweating (hyperhidrosis)

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Tramadol Hydrochloride 50mg Capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 50 mg tramadol hydrochloride (equivalent to 43.9 mg of

tramadol base)

For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Capsule

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Tramadol capsules are indicated for the management (treatment and prevention) of

moderate to severe pain.

4.2

Posology and method of administration

Posology

As with all analgesic drugs, 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. A total daily oral dose of 400 mg should not be exceeded, except in special

circumstances.

Unless otherwise prescribed, tramadol should be administered as follows:

Adults and children aged 12 years and over

Acute pain:

An initial dose of 100 mg is usually necessary. This can be followed by doses of 50 or 100

mg at 4 – 6 hourly, intervals, and the duration of treatment should be matched to clinical

need (see section 5.1).

Pain associated with Chronic Conditions:

An initial dose of 50 mg is advised and then titrate dose according to pain severity. The need

for continued treatment should be assessed at regular intervals as withdrawal symptoms and

dependence have been reported (see section 4.4).

Paediatric population

Tramadol capsules are not suitable for children below the age of 12 years.

Older people

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 requirement.

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.

Method of administration

For oral administration

The capsules are to be taken whole, not divided or chewed, with sufficient liquid, with or

without food.

Duration of administration

Tramadol

should

under

circumstances

administered

longer

than

absolutely

necessary. If long-term pain treatment with tramadol 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.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed section

6.1.

Acute

intoxication

with

alcohol,

hypnotics,

analgesics,

opioids

other

psychotropic drugs.

Patients who are receiving monoamine oxidase (MAO) inhibitors or have taken

them in the last 14 days (see section 4.5).

Patients with epilepsy not adequately controlled by treatment.

For use in narcotic withdrawal treatment.

4.4

Special warnings and precautions for use

Tramadol may only be used with particular caution in opioid-dependant patients, patients with

head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the

respiratory centre or function, increased intracranial pressure.

In patients sensitive to opiates the product should only be used with caution.

Concomitant use of tramadol 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

tramadol 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).

Convulsions have been reported in patients receiving tramadol at the recommended dose

levels. The risk may be increased when doses of tramadol exceed the recommended upper

daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients

taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients

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

compelling circumstances.

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.

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

patients with a tendency to drug abuse or dependence, treatment with tramadol should only be

carried out for short periods 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.

Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid

agonist, tramadol cannot suppress morphine withdrawal symptoms.

CYP2D6 metabolism

Tramadol is metabolised by the liver enzymes 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

summarized below:

Population

Prevalence %

African/Ethiopian

African American

3.4% to 6.5%

Asian

1.2% to 2%

Caucasian

3.6% to 6.5%

Greek

6.0%

Hungarian

1.9%

Northern European

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.

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

‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

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

In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine,

life-threatening interactions on the central nervous system, respiratory and cardiovascular

function have been observed. The same interactions with MAO inhibitors cannot be ruled out

during treatment with tramadol.

Concomitant administration of tramadol with other centrally acting depressant medicinal

products including alcohol may potentiate the CNS effects (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).

The results of pharmacokinetics studies have so far shown that on the concomitant or previous

administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to

occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may

reduce the analgesic effect and shorten the duration of action.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake

inhibitors

(SSRIs),

serotonin-norepinephrine

reuptake

inhibitors

(SNRIs),

tricyclic

anti-

depressants, anti-psychotics 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 ocular clonus.

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment

depends on the type and severity of the symptoms.

Caution should be exercised during concomitant treatment with tramadol and coumarin

derivatives

(e.g.

warfarin)

reports

increased

with

major

bleeding

ecchymoses in some patients.

Other active substances known to inhibit CYP3A4, such as ketoconazole, ritonavir and

erythromycin, might inhibit the metabolism of tramadol (N-demethylation) and probably the

metabolism of the active O-demethylated metabolite. The clinical importance of such an

interaction has not been studied (see section 4.8).

In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3

antagonist ondansetron increased the requirement of tramadol in patients with postoperative

pain.

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. There is inadequate

evidence available on the safety of tramadol in human pregnancy. Therefore tramadol should

not be used 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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.

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

Even when taken according to instructions, tramadol may cause effects such as

somnolence and dizziness and therefore may impair the reactions of drivers and

machine operators. This applies particularly in conjunction with other psychotropic

substances, particularly alcohol.

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’) if:

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 undesirable effects are classified into system organ classes and their frequency is

classified as follows:

Very common:

1/10

Common:

1/100, <1/10

Uncommon:

1/1,000, <1/100,

Rare:

1/10,000, < 1,000)

Very rare: < 1/10,000

Not known: cannot be estimated from the available data

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

more than 10% of patients.

Cardiac disorders:

Uncommon: cardiovascular regulation (palpitation, tachycardia). These adverse effects may

occur especially with intravenous administration and in patients who are physically stressed.

Rare: bradycardia.

Investigations:

Rare: increase in blood pressure

Vascular disorders:

Uncommon:

cardiovascular

regulation

(postural

hypotension

or cardiovascular

collapse).

These adverse reactions may occur especially on intravenous administration and in patients

who are physically stressed.

Respiratory, thoracic and mediastinal disorders:

Rare: respiratory depression, dyspnoea.

If the recommended doses are considerably exceeded and other centrally acting 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.

Nervous System disorders:

Very common: dizziness

Common: headache, somnolence

Rare:

paraesthesia,

tremor,

epileptiform

convulsions,

involuntary

muscle

contractions,

abnormal coordination, syncope, speech disorders.

Convulsions

occurred

mainly

after

administration

high

doses

tramadol

after

concomitant treatment with medicinal products which can lower the seizures threshold (see

sections 4.4 and 4.5).

Psychiatric disorders:

Rare: hallucinations, confusion, delirium, sleep disturbances, anxiety and nightmares. Psychic

side-effects 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

(usually

elation,

occasionally

dysphoria), changes in

activity

(mostly

reduced, occasionally increased) and changes in cognitive and sensorial ability (e.g. decision

behaviour, perception disorders). Drug dependence may occur.

Symptoms of withdrawal syndrome, similar to those occurring during opiate withdrawal, may

occur

follows:

agitation,

anxiety,

nervousness,

insomnia,

hyperkinesia,

tremor

gastrointestinal 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).

Eye disorders:

Rare: miosis, mydriasis, blurred vision.

Gastrointestinal disorders:

Very common: nausea.

Common: vomiting, constipation, dry mouth.

Uncommon:

retching,

gastrointestinal

irritation

feeling

pressure

stomach,

bloating), diarrhoea.

Skin and subcutaneous tissue disorders:

Common: hyperhidrosis

Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal and connective tissue disorders:

Rare: motorial weakness.

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.

Renal and urinary disorders:

Rare: micturition disorders, dysuria and urinary retention).

Metabolism and nutrition disorders:

Rare: changes in appetite

Not known: hypoglycaemia

General disorders:

Common: fatigue

Immune System Disorders

Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and

anaphylaxis.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

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

In principle, on intoxication with tramadol symptoms similar to those of other

centrally acting analgesics (opioids) are to be expected. These include in particular

miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma,

convulsions and respiratory depression up to respiratory arrest.

Treatment

The general emergency measures apply. Keep open the respiratory tract (aspiration),

maintain respiration and circulation depending on symptoms. The antidote for

respiratory depression is naloxone. In animal experiments naloxone had no effect on

convulsions. In such cases diazepam should be given intravenously.

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 formulation.

Tramadol is minimally eliminated from the serum by haemodialysis or haemo-

filtration. Therefore treatment of acute intoxication with Tramadol with haemodialysis

or haemo-filtration alone is not suitable for detoxification.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: other opioids; ATC code: N02A X02.

Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at

opioid receptors with a higher affinity for the

receptor. Other mechanisms

which may contribute to its analgesic effect are inhibition of neuronal reuptake of

noradrenaline and enhancement of serotonin release.

Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of

tramadol

over

wide

range

have

respiratory

depressant

effect.

Also

gastrointestinal motility is less affected. Effects on the cardiovascular system tend to

be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth)

that 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 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

More than

of tramadol

absorbed

after

oral

administration. The

mean

absolute

bioavailability is approximately 70%, irrespective of the concomitant intake of food. The

difference between absorbed and non-metabolised available tramadol is probably due to the

low first-pass effect. The first-pass effect after oral administration is a maximum of 30%.

Tramadol has a high tissue affinity (V d

= 203 ± 40 L). It has a plasma protein binding of

about 20%.

Following a single oral dose administration of tramadol 100 mg as capsules or tablets to

young healthy volunteers, plasma concentration were detectable within approximately 15 to

45 minutes within a mean C

of 280 to 208 mcg/L and T

of 1.6 to 2 h.

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

and its O-desmethyl derivative are found in the breast-milk (0.1% and 0.02% respectively of

the applied dose).

Elimination

half-life

t1/2,

approximately

hours,

irrespective

mode

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

approximately 1.4.

humans

tramadol is mainly

metabolised

means of

O-demethylation

conjugation

O-demethylation

products

with

glucuronic

acid.

Only

desmethyltramadol

pharmacologically

active.

There

considerable

inter-individual

quantitative differences between the other metabolites. So far, eleven metabolites have been

found in the urine. Animal experiments have been shown that O-desmethyltramadol is more

potent than the parent substance by the factor 2 - 4. Its half-life t1/2,

(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.

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 (O-

desmethyltramadol), in an extreme case 22.3 h and 36 h respectively, have been determined.

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

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

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-desmthlytramadol 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 characterised. Information from studies

including

this age

group

indicates that the formation rate

O-desmethyltramadol

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

immature

renal

function

result

slow

elimination

accumulation

desmethyltramadol in children under 1 year of age.

5.3

Preclinical safety data

On repeated oral and parenteral administration of tramadol for 6 - 26 weeks in rats

and dogs and oral administration for 12 months in dogs haematological, clinico-

chemical and histological investigations showed no evidence of any substance-related

changes. Central nervous manifestations only occurred after high doses considerably

above the therapeutic range: restlessness, salivation, convulsions, and reduced weight

gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight

respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.

In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams

and raised neonate mortality. In the offspring retardation occurred in the form of

ossification disorders and delayed vaginal and eye opening. Male fertility was not

affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a

reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg

upwards and skeletal anomalies in the offspring.

In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies

showed no such effects. According to knowledge gained so far, tramadol can be

classified as non-mutagenic.

Studies on the tumorigenic potential of tramadol hydrochloride have been carried out

in rats and mice. The study in rats showed no evidence of any substance-related

increase in the incidence of tumours. In the study in mice there was an increased

incidence of liver cell adenomas in male animals (a dose-dependent, non-significant

increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females

of all dosage groups (significant, but not dose-dependent).

6.1

List of excipients

Calcium hydrogen phosphate dihydrate

Magnesium stearate

Colloidal anhydrous silica

TRAMADOL CAPSULES 50MG

PL 20117/0086

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 12

Steps taken after authorisation – summary

Summary of Product Characteristics

Page 13

Product Information Leaflet

Page 19

Labelling

Page 21

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

TRAMADOL CAPSULES 50MG

PL 20117/0086

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Morningside

Healthcare Limited a Marketing Authorisation for the medicinal product Tramadol Hydrochloride

50mg Capsules (PL 20117/0086) on 16 March 2012. Tramadol Hydrochloride 50mg Capsules is a

prescription only Medicine (POM).

Tramadol Hydrochloride 50mg Capsules is indicated for the treatment of moderate to severe pain.

The active ingredient, tramadol hydrochloride belongs to a group of medicines known as opioids

which act on the central nervous system. These relieve pain by acting on specific nerve cells of the

spinal cord and brain.

No new or unexpected safety concerns arose from this application and it was, therefore, judged that

the benefits of taking Tramadol Hydrochloride 50mg Capsules outweigh the risks; hence Marketing

Authorisation was granted.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

TRAMADOL HYDROCHLORIDE 50MG CAPSULES

PL 20117/0086

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment

Page 11

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted

Morningside

Healthcare Limited

a Marketing Authorisation for the medicinal product Tramadol Hydrochloride

50mg Capsules (PL 20117/0086) on 16 March 2012.

Tramadol Hydrochloride 50mg Capsules is a prescription only Medicine (POM) and is indicated

for the treatment of moderate to severe pain.

This application was submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming

to be a generic medicinal product of Tramal 50mg Capsules

(Grunethal GmbH, Germany), which

was first authorised in Germany in 1980. The corresponding reference product in the UK is Zydol

50mg Capsules (PL 00020/0197; G D Searle & Co. Limited, UK), which was first authorised in the

UK on 21 April 1994. This licence then underwent a change of ownership to Monsanto PLC (PL

08821/0005) on 20 December 1995.

The active ingredient, tramadol hydrochloride is an analgesic which belongs to the opioid family of

compounds and is used to treat moderate to severe pain. It is an opioid receptor agonist and

noradrenaline reuptake inhibitor.

Tramadol

hydrochloride

produces

analgesia

mechanisms;

opioid

effect

enhancement of serotonergic and adrenergic pathways.

No new non-clinical data have been submitted, which is acceptable given that the application was

based on being a generic medicinal product of an originator product that has been in clinical use for

over 10 years.

A single-dose

bioequivalence study, was submitted to support this application, comparing the

pharmacokinetic profile of the test product, Tramadol Hydrochloride 50mg Capsules (Morningside

Healthcare Limited), versus the reference product, Tramal 50mg Capsules (Grunethal GmbH,

Germany). The bioequivalence study was carried out in accordance with Good Clinical Practice

(GCP).

With the exception of the bioequivalence study, no new clinical studies were performed, which is

acceptable given that the application was based on being a generic medicinal product of an

originator product that has been in clinical use for over 10 years.

No new or unexpected safety concerns arose during review of information provided by the

Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Tramadol

Hydrochloride 50mg Capsules outweigh the risks; hence the Marketing Authorisation was granted.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

PHARMACEUTICAL ASSESSMENT

ACTIVE SUBSTANCE

INN:

Tramadol hydrochloride

Chemical Name:

RS

RS

)-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol

hydrochloride

Structure:

Molecular Formula:

ClNO

Molecular weight:

299.8

Appearance:

A white, bitter, odourless, crystalline powder. It is readily soluble in water

and ethanol.

Tramadol hydrochloride is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance tramadol hydrochloride are

covered by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability.

Suitable specifications have been provided for all packaging used. The primary packaging has been

shown to comply with current guidelines concerning contact with foodstuff.

Appropriate stability data have been generated to support a suitable retest periods for the active

substance when stored in the proposed packaging.

DRUG PRODUCT

Other Ingredients

Other ingredients consist of the pharmaceutical excipients, namely croscarmellose sodium,

povidone (polyvinylpyrrolidone), microcrystalline cellulose, silicon dioxide, magnesium stearate,

gelatin, titanium dioxide (E171), yellow iron oxide (E172), quinoline yellow (E104) and brilliant

blue FD&C No.1 (E133). Appropriate justifications for the inclusion of each excipient have been

provided.

All excipients comply with their respective European Pharmacopoeia monographs, with the

exception of yellow iron oxide (E172), quinoline yellow (E104) and brilliant blue FD&C No.1

(E133). Yellow iron oxide (E172) is controlled to its respective National Formulary specifications.

Quinoline yellow (E104), yellow iron oxide (E172) and brilliant blue FD&C No.1 (E133) are also

in compliance with current European Directives concerning use of colouring agents in foodstuff.

Satisfactory Certificates of Analysis have been provided for all excipients, showing compliance

with the proposed specifications.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

With the exception of gelatin and magnesium stearate, none of the excipients used contain materials

of animal or human origin. All suppliers of gelatin and magnesium stearate have provided TSE

Certificates of Suitability to show that appropriate measures are taken to reduce the risk of

transmission of BSE/TSE, in line with current EU regulations.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious, stable product that

could be considered a generic medicinal product of Tramal 50mg Capsules (Grunethal GmbH,

Germany).

Suitable pharmaceutical development data have been provided for this application.

Comparative dissolution and impurity profiles have been provided for this product and the

respective reference product.

Manufacturing Process

Satisfactory batch formula has been provided for the manufacture of product, along with an

appropriate account of the manufacturing process. The manufacturing process has been validated at

commercial scale and has shown satisfactory results. In addition confirmation has been provided

that process validation studies will be performed on full scale production batches, in accordance

with the process validation protocol.

Finished Product Specification

The finished product specification is satisfactory. Test methods have been described and adequately

validated, as appropriate. Batch data have been provided and comply with the release

specifications. Certificates of Analysis have been provided for any working standards used.

Container Closure System

The finished product is packaged in aluminium/polyvinylchloride blister packs. The blister strips

are packed in cardboard cartons and are available in pack sizes of 10, 20, 30, 40, 50, 60, 70, 80, 90

and100 capsules.

Not all pack sizes may be marketed. However, the Marketing Authorisation holder has committed

to submitting mock-ups to the UK regulatory authorities for approval before marketing any pack

size.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with foodstuff.

Stability

Finished product stability studies were performed in accordance with current guidelines on batches

of finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 4

years with the storage conditions ‘Store below 25

C, in the original package, to protect from

moisture and light’ has been accepted.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in

the bioequivalence study.

Summaries of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and

Labelling

The SmPC, PIL and labelling are satisfactory.

A package leaflet has been submitted to the MHRA along with results of consultations with target

patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as

amended. The results indicate that the package leaflet is well-structured and organised, easy to

understand and written in a comprehensive manner. The test shows that the patients/users are able

to act upon the information that it contains.

MAA Forms

The MAA form is satisfactory.

Expert Report

The quality overall summary is written by an appropriately qualified person and is a suitable

summary of the pharmaceutical aspects of the dossier.

Conclusion

The grant of Marketing Authorisation is recommended.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

NON-CLINICAL ASSESSMENT

PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY

As the pharmacodynamic, pharmacokinetic and toxicological properties of tramadol hydrochloride

are well-known, no further non-clinical studies are required and none have been provided.

NON-CLINICAL EXPERT REPORT

The non-clinical overview has been written by an appropriately qualified person and is a suitable

summary of the non-clinical aspects of the dossier.

ENVIRONMENTAL RISK ASSESSMENT

Suitable justification has been provided for non-submission of an Environmental Risk Assessment.

As the product is intended for generic substitution with a product that is already marketed, no

increase in environmental burden is anticipated. Thus, the justification for non-submission of an

Environmental Risk Assessment is accepted.

CONCLUSION

The grant of Marketing Authorisation is recommended.

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY

The clinical pharmacology of tramadol hydrochloride is well-known. With the exception of data

from the below bioequivalence study, no new pharmacodynamic or pharmacokinetic data are

provided or required for this application.

Pharmacokinetics

In support of this application, the Marketing Authorisation Holder has conducted an open-label,

randomised,

single-dose,

crossover, two period bioequivalence study comparing the test product

Tramadol Hydrochloride 50mg Capsules versus the reference product Tramal 50mg Capsules

(Grunethal GmbH, Germany) in healthy adult male subjects under fasted conditions. The objective

of the pharmacokinetic study was to assess bioequivalence between the reference formulation and

the test formulation, under fasting conditions after single oral administration.

All volunteers received a single oral dose of either the test or the reference product with 200ml of

water, under fasted conditions. Blood samples were taken for the measurement of pharmacokinetic

parameters pre-dose and up to 48 hours post dose. The washout period between the two treatment

arms was one week.

Results for main pharmacokinetic parameters:

Test versus. Reference formulation

Geometric Least Squares Mean

Parameters

Reference product

(

Tramal 50mg

Capsules

)

Test product

(

Tramadol

Hydrochloride

50mg Capsules

)

Ratio

(test/reference)

%

90% CI

C

max

(ng/ml)

156.836

(30.332)

168.032

(43.318)

105.69

97.92-114.07%

AUC

0-t

(ng.h/ml)

1057.539

(441.896

1079.848

(481.288)

101.39

96.15-106.92%

AUC

0-∞

(ng.h/ml)

1199.0689

(508.362)

1220.769

(534.696)

101.40

96.73-106.31%

C

max

maximum plasma concentration

AUC

0-t

area under the plasma concentration-time curve from time zero to t hours

AUC

0-∞

area under the plasma concentration-time curve from time zero to infinity

90% CI

geometric confidence interval (CI) calculated from ln-transformed data

The 90% confidence intervals for AUC and C

for test versus reference product for tramadol

hydrochloride are within the acceptance criteria specified in the

Note for Guidance on the

Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98)

. Thus, the data

support the claim that the test product Tramadol Hydrochloride 50mg Capsules (Morningside

Healthcare Limited) is bioequivalent to the reference product Tramal 50mg Capsules (Grunethal

GmbH, Germany).

Tramadol Hydrochloride 50mg Capsules

PL 20117/0086

EFFICACY

The efficacy of tramadol hydrochloride is well-known. No new efficacy data have been submitted

and none are required for application of this type.

SAFETY

With the exception of the safety data generated during the bioequivalence study, no new safety data

were submitted and none are required for application of this type. No new or unexpected safety

issues were raised by the bioequivalence study.

SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION

LEAFLET (PIL) AND LABELLING

The SmPC, PIL and labelling are clinically acceptable. The SmPC is consistent with these for the

reference product. The PIL is consistent with the details in the SmPC and in-line with the current

guidelines. The labelling is in-line with the current guidelines.

CLINICAL EXPERT REPORT

The clinical overview is written by an appropriately qualified physician and is a suitable summary

of the clinical aspects of the dossier.

PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN

The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides

adequate evidence that the applicant has the services of a qualified person responsible for

pharmacovigilance, and has the necessary means for the notification of any adverse reaction

suspected of occurring either in the Community or in a third country.

Suitable justification has been provided for not submitting a risk management plan for this product.

CONCLUSION

The grant of Marketing Authorisation is recommended.

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