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TRAMELENE FLASHTAB 50MG ORODISPERSIBLE TABLETS

Active substance(s): TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
TRAMELENE FLASHTAB 50 mg orodispersible tablet

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50 mg of tramadol hydrochloride.
Excipient with known effects: each tablet also includes 20 mg of aspartame (E951).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Orodispersible tablet.
Round, white, biconcave tablet, engraved ‘T’ on one side and ‘50’ on the other
side, with a characteristic mint flavour.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Management (treatment and prevention) 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.
Adults and adolescents aged 12 years and over
For oral use:

Acute pain:
An initial dose is 50-100 mg depending on the intensity of pain. This can be followed
by doses of 50 or 100 mg 6 hours later, and duration of therapy should be matched to
clinical need. A total daily dose of 400 mg should not be exceeded except in special
clinical circumstances.
Pain associated with chronic conditions:
Use an initial dose of 50 mg and then titrate dose according to pain severity. The
initial dose may be followed if necessary by 50-100 mg every 6 hours. The
recommended doses are intended as a guideline. Patients should always receive the
lowest dose that provides effective pain control. A total daily dose of 400 mg should
not be exceeded except in special clinical circumstances. The need for continued
treatment should be assessed at regular intervals as withdrawal symptoms and
dependence have been reported (see section 4.4).
Elderly patients:
A dose adjustment is not usually necessary in patients up to 75 years without
clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years
elimination may be prolonged. Therefore, if necessary the dosage interval is to be
extended according to the patient's requirements.
Patients with hepatic and renal 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.
Paediatric population:
Tramelene Flashtab is not recommended in children aged under 12 years.
Method of administration
The tablet disperses rapidly in the mouth and is then swallowed. Then, this is washed
down with a glass of water. Alternatively the tablet can be dispersed in half a glass of
water, stirred and drunk immediately.

4.3

Contraindications
Tramelene Flashtab must not be administered to patients who have previously
demonstrated hypersensitivity to the active substance or to any of the excipients listed
in section 6.1.
The product must not be administered to patients suffering from acute intoxication or
overdose with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic
drugs. In common with other opioid analgesics it must not be administered to patients
who are receiving monoamine oxidase inhibitors or within two weeks of their
withdrawal. It must not be administered concomitantly with nalbuphine,
buprenorphine or pentazocine (see section 4.5).
Contraindicated in patients suffering from uncontrolled epilepsy.
Tramelene Flashtab should not be administered during breast feeding if long term
treatment, i.e. more than 2-3 days, is necessary.

Tramelene Flashtab is not suitable for children under 12 years of age.

4.4

Special warnings and precautions for use
Warnings:
At therapeutic doses, Tramelene Flashtab has the potential to cause withdrawal
symptoms. Rarely cases of dependence and abuse have been reported.
However, Tramelene Flashtab should only be used for short periods and under
strict medical supervision in patients with a tendency of drug abuse or
dependence.
At therapeutic doses withdrawal symptoms have been reported at a reporting
frequency of 1 in 8,000. Reports of dependence and abuse have been less
frequent. Because of this potential the clinical need for continued analgesic
treatment should be reviewed regularly. In patients with a tendency to drug
abuse or dependence, treatment should be for short periods and under strict
medical supervision.
Tramelene Flashtab is not suitable as a substitute in opioid-dependent patients.
Although it is an opioid agonist, it cannot suppress morphine withdrawal
symptoms.
Alcohol intake and concomitant use of carbamazepine are not recommended
during the treatment.
Precautions:
Tramelene Flashtab should be used with caution in patients with head injury,
increased intracranial pressure, impairment of hepatic and renal function,
decreased level of consciousness and in patients prone to convulsive disorders
or in shock.
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).
At the recommended doses Tramelene Flashtab is unlikely to produce
clinically relevant respiratory depression. However, care should be taken when
treating patients with existing respiratory depression, or excessive bronchial
secretion and in those patients taking concomitant CNS depressant drugs.
The ingredient aspartame contains a source of phenylalanine which may be
harmful to people with phenylketonuria.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of the following is contraindicated:
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
(risk of serotonergic syndrome – see below). The possibility of similar interactions
occurring between monoamine oxidase inhibitors (including the selective MAO A
and B inhibitors and linezolid) and tramadol cannot be ruled out.
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 and
that a withdrawal syndrome may occur.
Concomitant use of the following needs to be taken into consideration:
Tramadol can induce convulsions and increase the potential for selective serotonin
reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants, antipsychotics and other seizure threshold-lowering
medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause
convulsions.
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine
may cause serotonin toxicity. Serotonin syndrome is likely when one of the
following is observed:
• Spontaneous clonus
• Inducible or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature > 38 °C and inducible or ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement.
Treatment depends on the type and severity of the symptoms.
Concomitant administration of Tramelene Flashtab with other centrally acting drugs
(including other opioid derivatives, benzodiazepines, barbiturates, other anxiolytics,
hypnotics, sedative anti-depressants, sedative anti-histamines, neuroleptics, centrally
acting anti-hypotensive drugs, baclofen and alcohol), may potentiate CNS depressant
effects including respiratory depression.
Simultaneous administration of carbamazepine markedly decreases serum
concentrations of tramadol to an extent that a decrease in analgesic effectiveness and
a shorter duration of action may occur.
There have been isolated reports of interaction with coumarin anticoagulants resulting
in an increased international normalised ratio (INR) and so care should be taken when
commencing treatment with tramadol in patients on anticoagulants.
The analgesic effect of tramadol is in part mediated by the inhibition of the re-uptake
of nor-epinephrine 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 post operative pain".

4.6

Fertility, pregnancy and lactation

Pregnancy:
In humans, there are no sufficient data to assess malformative effect of tramadol
when given during the first trimester of pregnancy. Animal studies have not shown
any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity
appeared (see section 5.3).
Tramadol crosses the placenta, therefore as with other opioid analgesics, chronic use
of tramadol during the third trimester may induce a withdrawal syndrome in newborn.
At the end of pregnancy, high dosages, even for short term treatment, may induce
respiratory depression in newborn.
There is inadequate evidence available on the safety of tramadol in human pregnancy,
therefore Tramelene Flashtab should not be used in pregnant woman.
Breast-feeding:
Tramadol and its metabolites are found in small amounts in human breast milk. An
infant could ingest 0.1 % of the dose given to the mother. A single administration of
tramadol does not usually require breastfeeding to be interrupted. If repeated
administration is needed for several days, i.e. more than 2-3 days, breast feeding
should be suspended. Tramelene Flashtab should not be administered during breast
feeding if long term treatment is necessary.

4.7 Effects on ability to drive and use machines
Tramelene Flashtab may cause drowsiness and this effect may be potentiated by alcohol and
other CNS depressants. Ambulant patients should be warned not to drive or operate
machinery if affected.

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 you have this medicine in your body over a
specified limit unless you have a defence (called the ‘statutory defence’).
• This defence applies when:
o The medicine has been prescribed to treat a medical or dental problem; and
o You have taken it according to the instructions given by the prescriber and in
the information provided with the medicine.
• Please note that it is still an offence to drive if you are unfit because of the
medicine (i.e. your ability to drive is being affected).”
Details regarding a new driving offence concerning driving after drugs have been
taken in the UK may be found here: https://www.gov.uk/drug-driving-law

4.8

Undesirable effects
The table below presents possible adverse drug reactions in system organ class
order and sorted by frequency.
The following frequency convention is used in the evaluation of undesirable
effects:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known
(cannot be estimated form the available data).

Organ System

Frequency

Immune system
disorders

Rare

Adverse drug reaction
- allergic reactions (e.g. dyspnoea,
bronchospasm, wheezing, angioneurotic
oedema) and anaphylaxis.

Metabolism and
Rare
Nutrition disorders

- changes in appetite.

Psychiatric
disorders

Rare

The following may vary in nature and
intensity depending on the individual:
- changes in mood (e.g. elation, dysphoria)
- changes in activity (e.g. suppression,
increase)
- change in cognitive and sensorial
capacity (e.g. decision behaviour,
perception disorders)
- hallucinations
- confusion
- sleep disturbances
- anxiety
- nightmares
- dependency

Very Common

- dizziness

Common
Nervous system
disorders
Rare

Eye disorders

Rare

- headache
- drowsiness
- epileptiform convulsions (see sections 4.4
and 4.5)
- paraesthesia
- tremor
- involuntary muscle contractions
- abnormal coordination
- blurred vision

Organ System

Cardiac disorders

Frequency

Uncommon

Rare

Adverse drug reaction
- cardiovascular regulation (e.g.
palpitation, tachycardia, postural
hypotension, cardiovascular collapse).
These effects may occur especially on
intravenous administration and in patients
who are physically stressed.
- bradycardia, increase in blood pressure

Vascular disorders Very rare

- flushing

Respiratory,
thoracic and
mediastinal
disorders

- worsening of asthma, respiratory
depression (see sections 4.4 and 4.5).

Gastrointestinal
disorders
Hepato-biliary
disorders
Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
Renal and urinary
disorders
General disorders

Very rare
Very Common
Common
Uncommon
Very rare
Common
Uncommon
Rare
Rare
Common

- vomiting, nausea
- constipation, dry mouth
- retching, gastrointestinal irritation (a
feeling of pressure in the stomach,
bloating), diarrhoea.
- increase in liver enzyme values (a few
isolated cases have been reported)
- sweating
- dermal reactions (e.g. pruritus, rash,
urticaria)
- motor weakness
- micturition disorders (difficulty in
passing urine and urinary retention)
- fatigue

Prolonged administration of Tramelene Flashtab 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.

4.9

Overdose
Symptoms
Symptoms of overdose are typical of other opioid analgesics, and include miosis,
vomiting, hypotension, cardiovascular collapse, sedation and coma, epileptic seizures
and respiratory depression. Respiratory failure may also occur.
Management

Supportive measures such as maintaining the patency of the airway and maintaining
cardiovascular function should be instituted; naloxone should be used to reverse
respiratory depression; fits can be controlled with diazepam. Naloxone administration
may increase the risk of seizures. The use of benzodiazepines (intravenously) should
be considered for patients with seizures.
Tramadol is minimally eliminated from the serum by haemodialysis or
haemofiltration. Therefore treatment of acute intoxication with Tramelene Flashtab
with haemodialysis or haemofiltration alone is not suitable for detoxification.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Analgesic, Other opioids
ATC code: N02AX02
Mechanism of action
Tramadol is a centrally acting analgesic. It is a non selective pure agonist at mu, delta
and kappa opioid receptors with a higher affinity for the mu receptor. Other
mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.
Clinical efficacy and safety
Tramadol has antitussive properties. Unlike morphine, tramadol does not depress
breathing over a wide range of analgesic doses. The effects of tramadol on the
cardiovascular system are comparatively small. The potency of tramadol is 1/10 to
1/6 that of morphine.

5.2

Pharmacokinetic properties
Absorption
After oral administration, tramadol is almost completely absorbed. Mean absolute
bioavailability is approximately 70% following a single dose and increases to
approximately 90% at steady state.
Following a single oral dose administration of tramadol 100 mg to young healthy
volunteers, plasma concentrations were detectable within approximately 15-45
minutes with a mean maximum plasma concentration Cmax of 280 to 308 ng/ml and
time to reach maximum plasma concentration Tmax of 1.6 to 2 hours.
In a specific study comparing the orodispersible tablets with immediate release
capsules, the administration of a single dose of 50 mg Tramelene Flashtab in healthy
volunteers produced a mean area under the plasma concentration-time curve (AUC)
1102 ± 357 ng.h/ml, a mean Cmax 141 ± 39 ng/ml, and a mean Tmax 1.5 hours. The
respective values for the reference product were AUC 1008 ± 285 ng.h/ml, Cmax 139
± 37 ng/ml and Tmax 1.5 hours. The 90% confidence intervals were 94-110% for Cmax
and 104-112% for AUC.

Distribution
Plasma protein binding of tramadol is approximately 20%. It is independent of the
plasma concentration of the drug within the therapeutic range.
Tramadol crosses the blood-brain barrier and the placental barrier. Tramadol and its
metabolite O-desmethyltramadol are detectable in breast milk in very small amounts
(0.1% and 0.02% of the administered doses, respectively).
Tramadol has a high tissue affinity, with an apparent volume of distribution of 3 to 4 l/kg.
Biotransformation
Tramadol is metabolised by cytochrome P450 isoenzyme CYP2D6. It undergoes
biotransformation to a number of metabolites mainly by means of N- and Odemethylation. O-desmethyl tramadol appears to be the most pharmacologically
active metabolite, showing analgesic activity in rodents. It is 2 to 4 times more active
than tramadol.
As humans excrete a higher percentage of unchanged tramadol than animals it is
believed that the contribution made by this metabolite to analgesic activity is likely to
be less in humans than animals. In humans the plasma concentration of this
metabolite is about 25% that of unchanged tramadol.
The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6
involved in the metabolism of tramadol, may affect the plasma concentration of
tramadol or its active metabolite. The clinical consequences of any such interactions
are not known.
Elimination
For tramadol, the terminal elimination half-life (t½β) was 6.0 ± 1.5 hours in young
volunteers. For O-desmethyltramadol, t½β (6 healthy volunteers) was 7.9 hours (range
5.4 – 9.6 hours).
When C14 labelled tramadol was administered to humans, approximately 90% was
excreted via the kidneys with the remaining 10% appearing in the faeces.
Tramadol pharmacokinetics show little age dependence in volunteers up to the age of
75 years. In volunteers aged over 75 years, t½β was 7.0 ± 1.6 hours on oral
administration.
Since tramadol is eliminated both metabolically and renally, the terminal half-life t½β
may be prolonged in impaired hepatic or renal function. However, the increase in the
t½β values is relatively low if at least one of these organs is functioning normally. In
patients with liver cirrhosis t½β tramadol was a mean of 13.3 ± 4.9 hours ; in patients
with renal insufficiency (creatinine clearance ≤ 5 ml/min) it was 11.0 ± 3.2 hours.
Pharmacokinetic/Pharmacodynamic relationship(s)
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The pharmacokinetic/pharmacodynamic relation is dose-dependent, but varies within
a wide range. Generally, a serum concentration between 100 to 300 ng/ml is effective.

5.3

Preclinical safety data
In single and repeat-dose toxicity studies (rodents and dogs) exposure to
tramadol 10 times that expected in man is required before toxicity
(hepatotoxicity) is observed. Symptoms of toxicity are typical of opioids and
include restlessness, ataxia, vomiting, tremor, dyspnoea and convulsions.
Exposure to tramadol (≤ that expected in man), in lifetime toxicity studies in
rodents did not reveal any evidence of carcinogenic hazard, and a battery of
in-vitro and in-vivo mutagenicity tests were negative.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Ethylcellulose,
Copovidone,
Silicon dioxide,
Mannitol (E421),
Crospovidone,
Aspartame (E951),
Mint rootbeer flavouring,
Magnesium stearate.

6.2

Incompatibilities
None known

6.3

Shelf life
3 years

6.4

Special precautions for storage
Store in the original package.

6.5

Nature and contents of container
Tablets in blister packs composed of two sheets:
- a complex of polyamide/aluminium/poly(vinyl chloride)
- a sheet of aluminium.
Boxes of 10, 20, 28, 30, 40, 50, 56, 60 and 100 tablets.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
ETHYPHARM
194 Bureaux de la Colline – Bâtiment D
92213 Saint-Cloud Cedex
FRANCE

8

MARKETING AUTHORISATION NUMBER(S)
PL 06934/0071

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/07/2009

10

DATE OF REVISION OF THE TEXT
15/01/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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