TRAFLASH 50 mg Orodispersible Tablet

Зміст інструкції

1. MEDICINE NAME
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. 2 Dosage and route of administration
5. 3 Contraindications
6. Special warnings and precautions for use
7. 5 Interactions with other medicinal products and other forms of interaction
8. 6 Fertility, pregnancy and lactation
9. 7 Effects on the ability to drive and operate machinery
10. 8 Undesirable effects
11. 9 Overdosage
12. Pharmacokinetic Properties
13. 3 Preclinical safety data
14. 2 Incompatibilities
15. 3 Shelf life
16. 4 Special precautions for storage
17. 5 Nature and contents of the container
18. 6 Special precautions for disposal
19. MARKETING AUTHORISATION HOLDER
20. MARKETING AUTHORISATION NUMBER
21. DATE OF FIRST AUTHORISATION
22. DATE OF TEXT REVISION

SUMMARY OF PRODUCT CHARACTERISTICS

1. MEDICINE NAME

TRAFLASH 50 mg orally disintegrating tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of tramadol hydrochloride.
Excipients with known action:
aspartame and glucose.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orally disintegrating tablet.
Round, white, biconvex tablet with ‘T’ imprinted on one side and ‘50’ on the other side, with a
characteristic mint aroma.

4. CLINICAL INFORMATION

4.1. Therapeutic indications

Treatment of moderate to severe pain

4.2 Dosage and route of administration

Dosage
The dosage must be adapted to the intensity of the pain and the individual sensitivity of the patient. In
general, the minimum effective dose should be chosen.

Adults and adolescents over 12 years
For oral use:

Acute pain:
An initial dose of 50 – 100 mg depending on the intensity of the pain. This may be followed by
doses of 50 or 100 mg at intervals of no more than four hours, and the duration of therapy should
be based on therapeutic need. The total daily dose of 400 mg should not be exceeded unless under
particular clinical circumstances.

Pain associated with chronic conditions:
An initial dose of 50 mg which should then be adjusted according to the intensity of the pain. The initial
dose may be followed if necessary by a dose of 50-100 mg every 6 hours. The recommended doses
should be considered as a guideline. Patients should always receive the lowest dose that allows
effective pain control. The total daily dose of 400 mg should not be exceeded unless
under particular clinical circumstances. The need for continued treatment should be verified at
regular intervals as cases of dependence and withdrawal symptoms have been reported (see
section 4.4. Special warnings and precautions for use).

Paediatric population:
Traflash should not be used in children under 12 years of age, as safety and efficacy have not
been established.

Elderly patients:
Usually, no dose adjustment is necessary in patients up to 75 years of age in the absence of clinically
manifest hepatic or renal insufficiency. In elderly patients over 75 years of age, drug elimination may
be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's
needs.

Renal impairment/dialysis and hepatic impairment:
In patients with renal and/or hepatic impairment, the elimination of tramadol is delayed. In these
patients, a prolongation of the dosing intervals should be carefully evaluated taking into
account the patient's needs.
In patients with severe renal or hepatic impairment, the use of Traflash 50 mg orodispersible tablets
should be avoided.
Since tramadol is eliminated very slowly by haemodialysis or haemofiltration, post-dialysis administration is usually not
necessary to maintain analgesia.
Route of administration
The tablet should be rapidly dissolved in the mouth and swallowed, then the mouth should be rinsed with a
glass of water. Alternatively, the tablet can be dissolved in half a glass of water,
mixed and quickly drunk.

4.3 Contraindications

Hypersensitivity to the active substance tramadol, or to any of the excipients listed in section 6.1.
The product must not be administered to patients with acute intoxication or overdose of
alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.
Like other opioid analgesics, tramadol must not be administered to patients undergoing treatment with
monoamine oxidase inhibitors or within two weeks of discontinuation of such treatment. Tramadol must not be administered concurrently with nalbufine, buprenorphine and
pentazocine (see section 4.5, Interactions with other medicinal products and other forms of interaction).
Contraindicated in patients with uncontrolled epilepsy.
If long-term treatment is necessary, tramadol must not be
administered during breastfeeding.
Traflash must not be administered to children under 12 years of age.

4.4. Special warnings and precautions for use

Risk associated with the concomitant use of sedative medicines such as benzodiazepines or related medicines:

correlates:
The concomitant use of Traflash and sedative medicines such as benzodiazepines or medicines related to
them may cause sedation, respiratory depression, coma and death. Due to these risks, the
concomitant prescription with these sedative medicines should be reserved for patients for whom the
options of an alternative treatment are not possible. If it is decided to prescribe Traflash in
concomitance with sedative medicines, the lowest possible effective dose should be used and the duration
of treatment should be as short as possible.
Patients should be carefully evaluated for signs and symptoms of respiratory depression and
sedation. In this regard, it is strongly recommended to inform patients and those who care for them (where
applicable) to pay attention to these symptoms (see section 4.5).

Risk of tolerance, dependence and withdrawal symptoms:
At therapeutic doses, Traflash may cause withdrawal symptoms. Rare cases of
dependence and abuse have been reported. In any case, in patients with a tendency to drug abuse or
dependence, Traflash should be used only for short periods and under strict medical supervision.
Tolerance and physical and psychological dependence may develop, especially after long-term
therapy.
Withdrawal symptoms have been detected at therapeutic doses with a frequency of 1 in 8000 patients. The
cases of dependence and abuse detected are less frequent. Given this potential effect, the
clinical need for prolonged analgesic treatment should be regularly assessed. In
patients with a tendency to drug abuse or dependence, treatment should be carried out for
short periods and under strict medical supervision.
Traflash is not suitable as a substitute for patients with opioid dependence, as it does not antagonize
morphine withdrawal symptoms, despite being an opioid agonist. If a patient no longer
needs tramadol therapy, it may be advisable to gradually reduce the dose to prevent
withdrawal symptoms.

Serotonin syndrome
Serotonin syndrome, a potentially life-threatening condition, has been reported in patients treated with
tramadol in combination with other serotonergic agents or tramadol as monotherapy (see sections

• 4.5, 4.8 and 4.9). If concomitant treatment with other serotonergic agents is clinically justified, careful observation of the patient is recommended, particularly at the start of treatment and with dose increases. Symptoms of serotonin syndrome may include alterations in mental status, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered, depending on the severity of the symptoms. Discontinuation of serotonergic drugs

usually promotes rapid improvement.

CYP2D6 metabolism:
Tramadol is metabolized by the hepatic enzyme CYP2D6. If a patient shows a deficiency in
this enzyme or is completely lacking it, they may not obtain adequate analgesic effect. Estimates indicate that up to 7% of the Caucasian population may have this deficiency.
However, if the patient is an ultra-rapid metabolizer, there is a risk of developing adverse effects of opioid toxicity even at commonly prescribed dosages.
General symptoms of opioid toxicity include confusion, drowsiness, shallow breathing,
constricted pupils, nausea, vomiting, constipation and loss 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 the prevalence of ultra-rapid metabolizers in different populations
are summarized below:
Prevalence %
29 %
from 3.4% to 6.5%
from 1.2% to 2%
from 3.6% to 6.5%
6.0 %
1.9 %
from 1% to 2%
Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. The use of opioids increases the
risk of CSA in a dose-dependent manner. In patients who present with CSA, a reduction in the total dose of opioids should be considered.
Adrenal insufficiency
Opioid analgesics can occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include, for example, severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite and weight loss.
Paediatric population

Post-operative use in children
Published literature has reported that tramadol administered post-operatively in children following tonsillectomy and/or adenoidectomy for obstructive sleep apnea
has led to the occurrence of rare but life-threatening adverse events. Extreme caution should be exercised when tramadol is administered to children to relieve post-
operative pain and should be accompanied by careful monitoring of symptoms of opioid toxicity,
including respiratory depression.

Children with compromised respiratory function
The use of tramadol is not recommended in children in whom respiratory function may be
compromised, including neuromuscular diseases, severe cardiac or respiratory diseases, upper or lower respiratory tract infections,
Population
African/Ethiopian
African American
Asian
Caucasian
Greek
Hungarian
Northern European
multiple traumas or complex surgical procedures. These
factors may worsen symptoms of opioid toxicity.
The intake of alcohol and the concomitant use of carbamazepine should be avoided during
treatment with tramadol.

Precautions:
Traflash should be used with caution in patients with head injuries, increased intracranial
pressure, severe hepatic or renal insufficiency, reduced level of consciousness and in patients with a tendency
to seizures or in shock.
Cases of seizures have been reported at therapeutic doses of tramadol and the risk may be
increased following the administration of doses exceeding the total daily dose. Patients
with a history of epilepsy or those experiencing seizures should be treated with tramadol only in cases
of absolute necessity. The risk of seizures may increase in those patients who take
tramadol and drugs that can lower the seizure threshold concurrently (see
section 4.5, Interactions with other medicines and other forms of interaction).
The administration of Traflash at the recommended doses is unlikely to produce clinically relevant
respiratory depression. However, Traflash should be administered with caution to
patients with respiratory depression or excessive bronchial secretion and in patients who
are taking concomitant drugs that depress the central nervous system.

Information relating to excipients
The excipient aspartame contains a source of phenylalanine, potentially hazardous for people
affected by phenylketonuria, a rare genetic disease in which phenylalanine accumulates because
the organism cannot remove it correctly.
The mint flavour contains maltodextrins (glucose). Patients with sugar intolerance should not
take this medicine.

4.5 Interactions with other medicinal products and other forms of interaction

The drug must not be administered concurrently with other medicinal products in the following cases:
The lives of patients treated with monoamine oxidase inhibitors have been endangered within 14
days prior to the administration of the opioid pethidine, due to interactions at the level of the
central nervous system centers that regulate breathing and circulation (risk of serotonin syndrome – see below). The possibility of similar interactions occurring between monoamine oxidase inhibitors (including selective MAO A and B inhibitors and linezolid) and tramadol cannot be
excluded.
The combination of mixed/antagonist agonists (e.g. buprenorphine, nalbuphine, pentazocine) with
tramadol should be avoided because it is theoretically possible that in these circumstances the analgesic effect of a pure agonist is attenuated and withdrawal syndrome occurs.

Sedative medicinal products such as benzodiazepines or related medicinal products:
The concomitant use of opioids with sedative medicinal products such as benzodiazepines or medicinal products related
to them increases the risk of sedation, respiratory depression, coma and death due to the additional depressant effect on the CNS. The dose and duration of combined treatment must be limited
(see section 4.4).
The therapeutic use of tramadol in association with serotonergic drugs such as selective serotonin
reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors
(SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine,
can cause serotonin syndrome, a potentially life-threatening condition (see sections 4.4 and

• 4.8).

The concomitant administration of Traflash with other drugs that act at the central level (including
other opioid derivatives, benzodiazepines, barbiturates, other anxiolytics, hypnotics, sedative antidepressants,
sedative antihistamines, neuroleptics, central-acting antihypertensive drugs, baclofen and alcohol)
may potentiate the depressant effect on the central nervous system including respiratory depression.
The administration of Traflash in association with carbamazepine leads to a marked
reduction in serum tramadol concentrations, resulting in a possible reduction in the analgesic effect and a shorter duration of effect.
Tramadol can induce seizures and potentiate the effect of selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), antipsychotics and other drugs (such as bupropion, mirtazapine,
tetrahydrocannabinol) that lower the seizure threshold (see section 4.4 Special warnings and
precautions for use and section 5.2 Pharmacokinetic properties).
Isolated cases of interaction between tramadol and coumarin anticoagulants leading to
an increased INR (International Normalised Ratio) have been reported, therefore great caution should be exercised when
starting treatment with tramadol in patients treated with anticoagulants.
In a limited number of clinical studies, pre- or post-operative administration of the antiemetic
5-HT antagonist, ondansetron, has increased the requirement for tramadol in patients with post-operative pain.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are insufficient data on humans regarding a teratogenic effect of tramadol if administered during the first trimester of pregnancy. Animal studies have not shown teratogenic effects, but at high doses, fetotoxicity occurs due to maternal toxicity (see section 5.3 Preclinical safety data).
Tramadol crosses the placenta, like other opioid analgesics, therefore chronic use of tramadol during the third trimester can induce withdrawal syndrome in the newborn. At the end of pregnancy, high dosages, even for short periods, can induce respiratory depression in the newborn. Traflash must not be used during pregnancy as sufficient safety data on the use of tramadol in pregnancy are not available.

Lactation
Approximately 0.1% of the dose of tramadol taken by the mother is excreted in breast milk.
In the immediate postpartum period, for a maternal daily oral dose of up to 400 mg, this corresponds to an average amount of tramadol ingested by breastfed infants equal to 3% of the mother's weight-adjusted dose. For this reason, tramadol should not be used during lactation or, alternatively, lactation should be discontinued during treatment with tramadol. Discontinuation of lactation is not generally necessary following a single dose of tramadol.

4.7 Effects on the ability to drive and operate machinery

Traflash may cause drowsiness, an effect that may be enhanced by the concurrent use of
alcohol and other drugs that depress the central nervous system. Outpatients should be
warned not to drive or operate machinery if drowsiness occurs.

4.8 Undesirable effects

The following table presents the possible adverse drug reactions, ordered by organ class and
frequency.
Frequency:
Very common (  1/10), common (  1/100, <1/10), uncommon (  1/1.000, <1/100), rare (  1/10.000,
<1/1.000), very rare (<1/10.000), not known (the frequency cannot be defined on the basis of the available
data).

After administration of Tramadol, various psychic side effects may occur which
vary individually in intensity and nature (depending on personality and duration of
treatment). These effects include changes in mood (usually euphoria, occasionally
dysphoria), changes in activity (usually suppression, occasionally increase) and changes
in cognitive and sensory abilities (e.g. changes in decision-making abilities, perceptual disturbances),
hallucinations, confusion, sleep disorders and nightmares.
Prolonged administration of Traflash can lead to dependence (see section 4.4). The
withdrawal symptoms, similar to those following discontinuation of other opioid agents, may include: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and
gastrointestinal symptoms.
Very rarely, epileptic-type seizures have been reported after
administration of high doses of tramadol or after concomitant administration of drugs that
can lower the seizure threshold or that can themselves induce cerebral seizures (e.g.
antidepressants or antipsychotics, see section 4.5 Interactions with other medicines and other forms
of interaction).
Worsening of asthma has also been reported, although a causal relationship
has not been established. Respiratory depression has been reported. Respiratory depression may occur if
the recommended doses have been considerably exceeded and other centrally depressant drugs are administered concurrently (see section 4.5 Interactions with other medicines and
other forms of interaction).

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicinal
product is important, as it allows continuous monitoring of the benefit/risk ratio of the
medicinal product. Healthcare professionals are required to report any suspected adverse reaction via the
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .

4.9 Overdosage

The symptoms of an overdose are those typical of opioid analgesics and include miosis,
vomiting, hypotension, cardiovascular collapse, sedation and coma, convulsions and respiratory
depression. Respiratory failure may also occur. Serotonin syndrome has also been reported.
Supportive treatment in case of overdose involves maintaining airway patency and cardiovascular
function. Convulsive attacks can be controlled with
diazepam. Administration of naloxone may increase the risk of convulsions. The use of
benzodiazepines (intravenous administration) may be useful in patients with convulsions.
Tramadol is eliminated from the serum by hemodialysis or hemofiltration to a minimal extent. Therefore, the
treatment of an acute overdose of Traflash by hemodialysis or hemofiltration may not be sufficient
in itself.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic category
Analgesics, other opioids. ATC code: N02AX02.
Mechanism of action
Tramadol is a centrally acting analgesic. Tramadol is a pure, non-selective agonist for
mu, delta and kappa opioid receptors with greater activity towards the mu receptor. Other
mechanisms that may contribute to its analgesic effect include the inhibition of
neuronal reuptake of noradrenaline and increased release of serotonin.
Tramadol has antitussive properties. Unlike morphine, tramadol does not depress
respiration over a wide range of analgesic doses. The effects of tramadol on the cardiovascular
system are relatively modest. The potency of tramadol is between 1/10 and 1/6 of
that of morphine.
Paediatric population
The effects of enteral and parenteral administration of tramadol have been investigated in clinical
studies involving more than 2000 paediatric patients aged from neonatal age to 17
years. The indications for pain treatment studied in these clinical studies included pain
after surgery (especially abdominal), after surgical tooth extractions, caused
by fractures, burns and trauma and other painful conditions that may require analgesic treatment
for at least 7 days.
At single doses up to 2 mg/kg or multiple doses up to 8 mg/kg per day (up to a maximum of 400 mg
per day) tramadol was found to be more effective than placebo, and superior or equal to
paracetamol, nalbuphine, pethidine or low-dose morphine. The evidence conducted confirmed
the efficacy of tramadol. The safety profile of tramadol has proven to be similar in adult
and paediatric patients over 1 year of age (see section 4.2).

5.2. Pharmacokinetic Properties

Absorption
Following oral administration, tramadol is almost completely absorbed. The average absolute bioavailability
is approximately 70% after the administration of a single dose and increases
to approximately 90% at steady state.
After administration of a single oral dose of tramadol hydrochloride 100 mg in healthy volunteers, plasma
concentrations are detectable after approximately 15-45 minutes with a C average of 280-308
ng/ml and a T of 1.6-2 hours.
The results of a specific comparative study between orodispersible tablets and immediate-release capsules,
showed that the administration of a single dose of Traflash 50 mg in healthy
volunteers produces an average AUC of 1102 ± 357 ng/ml, an average C of 141 ± 39 ng/ml, and an average T
of 1.5 hours. This demonstrates bioequivalence compared to 50 mg immediate-release capsules (AUC 1008 ± 285 ng/ml, C 139 ± 37 ng/ml, T 1.5 hours).

Distribution
The binding of tramadol to plasma proteins is approximately 20% and is independent of
plasma drug concentration within its therapeutic range.
Tramadol crosses the blood-brain barrier and the placental barrier. Traces of tramadol and its metabolite,
O-desmethyl-tramadol, have been found in breast milk (respectively 0.1%
and 0.02% of the administered dose).

Biotransformation
Tramadol is metabolized by the cytochrome P450 isoenzyme CYP2D6. It undergoes biotransformation
into various metabolites predominantly through N- and O-demethylation. O-desmethyl tramadol
appears to be the pharmacologically most active metabolite, its analgesic activity having been demonstrated
in rodents. O-desmethyl tramadol is 2 to 4 times more active than tramadol.
Since a higher percentage of unchanged tramadol is excreted in humans
compared to animals, it is likely that the contribution of this metabolite to analgesic activity is lower in
humans than in animals. In humans, the plasma concentration of this metabolite is approximately 25%
compared to unchanged tramadol.
Inhibition of one or both of the P450 isoenzymes, CYP3A4 and CYP2D6, which are involved in
tramadol metabolism, may affect the plasma concentration of tramadol or its
active metabolite. The clinical effects of such interactions are not known.

Elimination
In healthy volunteers, the half-life (t ) is approximately 6 ± 1.5 hours. For O-desmethyl-tramadol, the half-life t (6
healthy volunteers) is 7.9 hours (range 5.4 – 9.6 hours).

Linearity/non-linearity
Within the therapeutic range, tramadol has a linear pharmacokinetic profile.
The PK/PD relationship is dose-dependent, but varies within a wide range. A
serum concentration of 100 – 300 ng/ml is generally effective.
Paediatric population
After the administration of a single dose and multiple doses to subjects aged between 1
year and 16 years, the pharmacokinetics of tramadol and O-demetiltramadol were generally
similar to those of adults when the dose was adjusted based on body weight, but with a more
high variability between subjects in children under 8 years of age.
The pharmacokinetics of tramadol and O-demetiltramadol have been studied in children under 1
year of age, but have not been fully characterized. Information obtained from studies
including this age group indicates that the frequency of O-demetiltramadol formation via
CYP2D6 increases continuously in newborns, and adult levels of CYP2D6 activity are presumed
to be reached at around 1 year of age. In addition, immature glucuronidation systems and an immature
renal function may cause slow elimination and accumulation of O-demetiltramadol in children under 1 year of age.

5.3 Preclinical safety data

In single and repeated dose toxicity studies (in rodents and dogs), an exposure to
tramadolo 10 times higher than in humans was required before observing toxicity at the hepatic level.
The symptoms of tramadolo toxicity are those typical of opioids and include agitation, ataxia,
vomiting, tremors, dyspnea and convulsions.
Exposure to tramadolo (> compared to humans), in studies conducted over the entire lifespan in rodents
did not reveal any evidence of carcinogenicity, and a set of in-vitroand in-

vivomutagenicity tests were negative.
In studies conducted on animals (rat and rabbit: the dose of tramadolo administered was seven times
higher than that administered to humans) did not reveal any teratogenic effects. Minimal embryotoxic effects (delayed ossification) were observed in the tests.
No effects on fertility or offspring development were observed.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients

Ethylcellulose, copovidone, silicon dioxide, mannitol (E421), crospovidone, aspartame (E951), mint flavor,
magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of the container

Tablets in a blister composed of two layers:

• polyamide/aluminum/polyvinyl chloride complex
• aluminum foil.

Pack sizes: 10, 20, 28, 30, 40, 50, 56, 60 and 100 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special instructions.

7. MARKETING AUTHORISATION HOLDER

Viatris Healthcare Limited
Damastown Industrial Park,
Mulhuddart, Dublin 15,
Dublin, Ireland

8. MARKETING AUTHORISATION NUMBER

10 tablets AIC n. 036672018
20 tablets AIC n. 036672020
28 tablets AIC n. 036672032
30 tablets AIC n. 036672044
40 tablets AIC n. 036672057
50 tablets AIC n. 036672069
56 tablets AIC n. 036672071
60 tablets AIC n. 036672083
100 tablets AIC n. 036672095

9. DATE OF FIRST AUTHORISATION

July 2005

10. DATE OF TEXT REVISION