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	Adverse drug reaction
Immune system disorders	Rare	- allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Metabolism and Nutrition disorders	Rare	- 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	-    headache -    drowsiness
Nervous system disorders	Rare	-    epileptiform convulsions (see sections 4.4 and 4.5) -    paraesthesia -    tremor -    involuntary muscle contractions -    abnormal coordination
Eye disorders	Rare	- blurred vision

Organ System	Frequency	Adverse drug reaction
Cardiac disorders	Uncommon	- 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.
	Rare	- bradycardia, increase in blood pressure
Vascular disorders	Very rare	- flushing
Respiratory, thoracic and mediastinal disorders	Very rare	- worsening of asthma, respiratory depression (see sections 4.4 and 4.5).
Gastrointestinal disorders	Very Common	- vomiting, nausea
	Common	- constipation, dry mouth
	Uncommon	- retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea.
Hepato-biliary disorders	Very rare	- increase in liver enzyme values (a few isolated cases have been reported)
Skin and subcutaneous tissue disorders	Common	- sweating
	Uncommon	- dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal and connective tissue disorders	Rare	- motor weakness
Renal and urinary disorders	Rare	- micturition disorders (difficulty in passing urine and urinary retention)
General disorders	Common	- 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 C_max of 280 to 308 ng/ml and time to reach maximum plasma concentration T_max 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 C_max 141 ± 39 ng/ml, and a mean T_max 1.5 hours. The respective values for the reference product were AUC 1008 ± 285 ng.h/ml, C_max 139 ± 37 ng/ml and T_max 1.5 hours. The 90% confidence intervals were 94-110% for C_max 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 O-demethylation. 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 (t_/2p) was 6.0 ± 1.5 hours in young volunteers. For O-desmethyltramadol, t_/p (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, t_/p was 7.0 ± 1.6 hours on oral administration.

Since tramadol is eliminated both metabolically and renally, the terminal half-life t/p may be prolonged in impaired hepatic or renal function. However, the increase in the t/p values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t_/p 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 - Batiment 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