Traflash

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

TRAFLASH 50 mg orodispersible tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

3. PHARMACEUTICAL FORM

Orodispersible tablet.
White, round, biconvex tablet, with 'T' engraved 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 Posology and method of administration
Posology
Dosage must be adjusted according to the intensity of pain and individual patient sensitivity. In general, the lowest effective dose should be chosen.
Adults and adolescents over 12 years of age
For oral use:
Acute pain:
An initial dose of 50 – 100 mg depending on the intensity of pain. This may be followed by doses of 50 or 100 mg no more frequently than every four hours. The duration of treatment should be based on therapeutic need. The total daily dose should not exceed 400 mg, except under special clinical circumstances.
Pain associated with chronic conditions:
An initial dose of 50 mg, subsequently adjusted according to pain intensity. This initial dose may be followed, if necessary, by doses of 50–100 mg every 6 hours. Recommended doses are intended as a guideline. Patients should always receive the lowest dose that provides effective pain control. The total daily dose should not exceed 400 mg, except under special clinical circumstances. The need for continued treatment should be reviewed regularly, as cases of dependence and withdrawal symptoms have been reported (see section 4.4. Special warnings and precautions for use).
Paediatric population:
Traflash must not be used in children under 12 years of age, as safety and efficacy have not been established.
Elderly patients:
Dosage adjustment is usually not required in patients up to 75 years of age in the absence of clinically evident hepatic or renal impairment. In elderly patients over 75 years, drug elimination may be slower. Therefore, if necessary, the dosing interval should be extended according to patient needs.
Renal impairment/dialysis and hepatic impairment:
In patients with renal and/or hepatic impairment, tramadol elimination is delayed. In these patients, careful consideration should be given to extending the dosing intervals according to patient needs.
In patients with severe renal or hepatic impairment, the use of Traflash 50 mg orodispersible tablets should be avoided.
Since tramadol is very slowly eliminated by haemodialysis or haemofiltration, post-dialysis administration is usually not necessary to maintain analgesia.
Method of administration
The tablet should be rapidly dissolved in the mouth and swallowed, followed by rinsing the mouth with a glass of water. Alternatively, the tablet may be dissolved in half a glass of water, stirred, 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 due to 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 (MAOIs) or within two weeks of discontinuation of such treatment. Tramadol must not be administered concomitantly with nalbuphine, buprenorphine, or 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 becomes 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 concomitant use of sedative medicinal products such as benzodiazepines or related medicines:
Concomitant use of Traflash and sedative medicinal products such as benzodiazepines or related medicines may cause sedation, respiratory depression, coma, and death. Due to these risks, concomitant prescription with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If concomitant prescription of Traflash with sedative medicines is decided, the lowest effective dose should be used and the duration of treatment should be as short as possible.
Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard, patients and caregivers (where applicable) should be strongly advised to be alert 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 only be used for short periods and under strict medical supervision.
Tolerance and physical and psychological dependence may develop, particularly following long-term therapy.
Withdrawal symptoms have been observed at therapeutic doses with a frequency of 1 in 8,000 patients. Cases of dependence and abuse are less frequent. Given this potential effect, the clinical need for prolonged analgesic treatment should be regularly evaluated. In patients with a tendency to drug abuse or dependence, treatment should be limited to short periods and under strict medical supervision.
Traflash is not suitable as a substitute for patients dependent on opioids, as it does not antagonize morphine withdrawal symptoms, despite being an opioid agonist. If a patient no longer requires tramadol therapy, gradual dose reduction may be advisable to prevent withdrawal symptoms.
Serotonin syndrome
Serotonin syndrome, a potentially life-threatening condition, has been reported in patients treated with tramadole 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 patient monitoring is advised, particularly at the beginning of treatment and during dose increases.
Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, dose reduction or discontinuation of therapy should be considered depending on the severity of symptoms. Discontinuation of serotonergic drugs usually leads to rapid improvement.
CYP2D6 metabolism:
Tramadol is metabolized by the hepatic enzyme CYP2D6. If a patient is deficient or completely lacks this enzyme, adequate analgesic effect may not be achieved. 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 opioid toxicity-related adverse effects even at commonly prescribed doses.
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 circulatory and respiratory depression, which can be life-threatening and very rarely fatal. Estimates of the prevalence of ultra-rapid metabolizers in various populations are summarized below:
Population Prevalence %
African/Ethiopian 29%
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%
Sleep-related breathing disorders
Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the total opioid dosage.
Adrenal insufficiency
Opioid analgesics may 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, reduced appetite, and weight loss.
Paediatric population
Post-operative use in children
Published literature includes reports of rare but life-threatening adverse events in children receiving tramadol post-operatively following tonsillectomy and/or adenoidectomy for obstructive sleep apnea. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief, and must be accompanied by careful monitoring for symptoms of opioid toxicity, including respiratory depression.
Children with compromised respiratory function
The use of tramadol is not recommended in children whose respiratory function may be compromised, including those with neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory or pulmonary infections, multiple traumas, or complex surgical procedures. These factors may worsen symptoms of opioid toxicity.
Alcohol consumption and concomitant use of carbamazepine must be avoided during tramadol treatment.
Precautions:
Traflash should be used with caution in patients with head injuries, increased intracranial pressure, severe hepatic or renal impairment, reduced level of consciousness, and in patients with a tendency to seizures or in shock.
Seizures have been reported at therapeutic doses of tramadol, and the risk may increase with doses exceeding the recommended total daily dose. Patients with a history of epilepsy or seizure disorders should only be treated with tramadol when absolutely necessary. The risk of seizures may increase in patients receiving tramadol concomitantly with drugs that lower the seizure threshold (see section 4.5, Interactions with other medicinal products and other forms of interaction).
Clinically relevant respiratory depression is unlikely to occur with Traflash administered at recommended doses. However, Traflash should be administered with caution in patients with respiratory depression or excessive bronchial secretion, and in patients taking concomitant central nervous system depressants.
Information on excipients
The excipient aspartame contains a source of phenylalanine, potentially hazardous for individuals with phenylketonuria, a rare genetic disorder in which phenylalanine accumulates because the body cannot properly remove it.
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 medicine must not be administered concomitantly with other medicines in the following cases:
Life-threatening situations have occurred in patients treated with monoamine oxidase inhibitors (MAOIs) within 14 days prior to administration of the opioid meperidine, due to central nervous system interactions affecting respiratory and circulatory control centres (risk of serotonin syndrome – see below). The possibility of similar interactions between MAOIs (including selective MAO A and B inhibitors and linezolid) and tramadol cannot be excluded.
The combination of mixed agonist/antagonist opioids (e.g., buprenorphine, nalbuphine, pentazocine) with tramadol should be avoided, as the analgesic effect of a pure agonist may theoretically be reduced and withdrawal syndrome may occur.
Medicinal products with sedative effects such as benzodiazepines or related medicines:
Concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma, and death due to additive CNS depressant effects. The dose and duration of combined treatment must be limited (see section 4.4).
Therapeutic use of tramadol in combination with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants, and mirtazapine may cause serotonin syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).
Concomitant administration of Traflash with other centrally acting drugs (including other opioid derivatives, benzodiazepines, barbiturates, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally acting antihypertensives, baclofen, and alcohol) may potentiate central nervous system depression, including respiratory depression.
Concomitant administration of Traflash with carbamazepine results in a marked reduction in tramadol serum concentrations, leading to a possible reduction in analgesic effect and shorter duration of action.
Tramadol may induce seizures and enhance the effects 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 have been reported, leading to increased INR (International Normalised Ratio); therefore, great caution should be exercised when initiating tramadol treatment in patients receiving anticoagulants.
In a limited number of clinical studies, pre- or post-operative administration of the antiemetic 5-HT3 antagonist ondansetron increased tramadol requirements in patients with post-operative pain.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are insufficient human data on the teratogenic effect of tramadol when 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 may induce neonatal withdrawal syndrome. At the end of pregnancy, high doses, even if administered for short periods, may cause respiratory depression in the newborn. Traflash must not be used during pregnancy, as sufficient safety data on tramadol use in pregnancy are not available.
Lactation
Approximately 0.1% of the tramadol dose taken by the mother is excreted in breast milk.
In the immediate postpartum period, with 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 dose adjusted for maternal weight. For this reason, tramadol must not be used during lactation or, alternatively, breastfeeding must be discontinued during tramadol treatment. Discontinuation of breastfeeding is generally not necessary following a single dose of tramadol.
4.7 Effects on ability to drive and use machines
Traflash may cause drowsiness, an effect that may be enhanced by concomitant alcohol consumption and other central nervous system depressants. Outpatients should be warned not to drive or operate machinery if drowsiness occurs.
4.8 Undesirable effects
The table below lists possible adverse drug reactions classified by organ system 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 (frequency cannot be estimated from the available data).

After administration of Tramadol, various psychological side effects may occur, which vary individually in intensity and nature (depending on personality and duration of treatment). These effects include mood changes (usually euphoria, occasionally dysphoria), changes in activity (usually suppression, occasionally increase), and alterations in cognitive and sensory functions (e.g. impaired decision-making, perceptual disturbances), hallucinations, confusion, sleep disturbances, and nightmares.

Prolonged administration of Traflash may lead to dependence (see section 4.4). Symptoms of withdrawal syndrome, similar to those observed after discontinuation of other opioid agents, may include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal symptoms.

Very rarely, epileptic-type seizures have been reported following administration of high doses of tramadol or concomitant administration of drugs that may lower the seizure threshold or that may themselves induce cerebral seizures (e.g. antidepressants or antipsychotics, see section 4.5 Interactions with other medicinal products and other forms of interaction).

Worsening of asthma has also been reported, although a causal relationship has not been established. Respiratory depression has been observed. Respiratory depression may occur if recommended doses are considerably exceeded and other centrally acting depressant drugs are administered concomitantly (see section 4.5 Interactions with other medicinal products and other forms of interaction).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after a medicinal product is authorised is important, as it allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .

4.9 Overdose
Symptoms of overdose are typical of opioid analgesics and include miosis, vomiting, hypotension, cardiovascular collapse, sedation and coma, seizures, and respiratory depression. Respiratory failure may also occur. Serotonin syndrome has also been reported.

Supportive treatment in case of overdose includes maintenance of airway patency and cardiovascular function. Seizure episodes may be controlled with diazepam. Administration of naloxone may increase the risk of seizures. The use of benzodiazepines (intravenous administration) may be beneficial in patients with seizures.

Tramadol is eliminated from serum only to a small extent by hemodialysis or hemofiltration. Therefore, treatment of acute Traflash overdose by hemodialysis or hemofiltration alone may not be sufficient.

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 non-selective pure agonist at mu, delta, and kappa opioid receptors, with higher activity at the mu receptor. Other mechanisms that may contribute to its analgesic effect include inhibition of neuronal noradrenaline reuptake and increased serotonin release.
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 that of morphine.

Paediatric population
The effects of oral and parenteral administration of tramadol have been investigated in clinical studies involving more than 2000 paediatric patients aged from neonatal age up to 17 years. Indications for pain treatment studied in these clinical trials included postoperative pain (especially abdominal surgery), pain following surgical dental extractions, pain due to 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), the efficacy of tramadol was shown to be superior to placebo and superior or equivalent to paracetamol, nalbuphine, pethidine, or low-dose morphine. Clinical trials have confirmed the efficacy of tramadol. The safety profile of tramadol has been shown to be similar in adult and paediatric patients over 1 year of age (see section 4.2).

5.2 Pharmacokinetic Properties
Absorption
After oral administration, tramadol is almost completely absorbed. The mean absolute bioavailability is approximately 70% after a single dose and increases to approximately 90% at steady state.
After a single oral dose of 100 mg tramadol hydrochloride in healthy volunteers, plasma concentrations are detectable after about 15–45 minutes, with a mean C_max of 280–308 ng/ml and a mean T_max of 1.6–2 hours.
Results from a specific comparative study between orodispersible tablets and immediate-release capsules showed that administration of a single 50 mg dose of Traflash in healthy volunteers produced a mean AUC of 1102 ± 357 ng·h/ml, a mean C_max of 141 ± 39 ng/ml, and a mean T_max of 1.5 hours. This demonstrates bioequivalence to 50 mg immediate-release capsules (AUC 1008 ± 285 ng·h/ml, C_max 139 ± 37 ng/ml, T_max 1.5 hours).

Distribution
Protein binding of tramadol 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 (approximately 0.1% and 0.02% of the administered dose, respectively).
Tramadol has high tissue affinity and an apparent volume of distribution of 3–4 l/kg.

Biotransformation
Tramadol is metabolized by the cytochrome P450 isoenzyme CYP2D6. It undergoes biotransformation into various metabolites, primarily via N- and O-demethylation. O-desmethyl-tramadol appears to be the pharmacologically most active metabolite, as analgesic activity has been demonstrated in rodents. O-desmethyl-tramadol is 2 to 4 times more potent than tramadol.
Since a higher proportion of unchanged tramadol is excreted in humans compared to animals, the contribution of this metabolite to analgesic activity is likely to be lower in humans than in animals. In humans, plasma concentration of this metabolite is approximately 25% of that of unchanged tramadol.
Inhibition of one or both P450 isoenzymes, CYP3A4 and CYP2D6, involved in tramadol metabolism, may affect plasma concentrations of tramadol or its active metabolite. The clinical effects of such interactions are unknown.

Elimination
In healthy volunteers, the elimination half-life (t_½) is approximately 6 ± 1.5 hours. For O-desmethyl-tramadol, the half-life (t_½) in 6 healthy volunteers was 7.9 hours (range 5.4 – 9.6 hours).
When radiolabelled C¹⁴-tramadol is administered to humans, approximately 90% is excreted renally and the remaining 10% in faeces.
Pharmacokinetic data for tramadol show minimal influence of age in volunteers up to 75 years. In volunteers over 75 years of age, the half-life (t_½) after oral administration was 7.0 ± 1.6 hours.
Since tramadol is eliminated both metabolically and renally, the half-life (t_½) may be prolonged in cases of hepatic or renal impairment. However, the increase in t_½ is relatively low if at least one of these two organs has normal function. In patients with hepatic cirrhosis, a half-life of 13.3 ± 4.9 hours was determined; in patients with renal failure (creatinine clearance ≤ 5 ml/min), values were 11.0 ± 3.2 hours.

Linearity/Non-linearity
Within the therapeutic range, tramadol exhibits linear pharmacokinetics.
The PK/PD relationship is dose-dependent but varies over a wide range. A serum concentration of 100–300 ng/ml is generally effective.

Paediatric population
After oral administration of single and multiple doses in subjects aged between 1 year and 16 years, the pharmacokinetics of tramadol and O-desmethyltramadol were generally similar to those in adults when the dose was adjusted according to body weight, although there was higher inter-individual variability in children under 8 years of age.
The pharmacokinetics of tramadol and O-desmethyltramadol have been studied in children under 1 year of age but have not been fully characterized. Data from studies including this age group indicate that the rate of formation of O-desmethyltramadol via CYP2D6 increases progressively in neonates, and adult levels of CYP2D6 activity are assumed to be reached at approximately 1 year of age. In addition, immature glucuronidation systems and immature renal function may lead to slow elimination and accumulation of O-desmethyltramadol in children under 1 year of age.

5.3 Preclinical Safety Data
In single and repeated-dose toxicity studies (in rodents and dogs), hepatic toxicity was observed only at exposures to tramadol approximately 10 times higher than those in humans.
Symptoms of tramadol toxicity are typical of opioids and include agitation, ataxia, vomiting, tremors, dyspnea, and convulsions.
Exposure to tramadol (> compared to humans) in lifetime studies in rodents did not reveal any evidence of carcinogenicity, and a battery of in-vitro and in-vivo mutagenicity tests yielded negative results.
Animal studies (rat and rabbit: the dose of tramadol administered was seven times higher than that given to humans) did not reveal teratogenic effects. Minimal embryotoxic effects (delayed ossification) were observed in 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 flavouring, magnesium stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original packaging.
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: EU/1/22/1558/001
20 tablets: EU/1/22/1558/002
28 tablets: EU/1/22/1558/003
30 tablets: EU/1/22/1558/004
40 tablets: EU/1/22/1558/005
50 tablets: EU/1/22/1558/006
56 tablets: EU/1/22/1558/007
60 tablets: EU/1/22/1558/008
100 tablets: EU/1/22/1558/009

9. DATE OF FIRST AUTHORIZATION

July 2005

10. DATE OF TEXT REVISION