Tapentadol Liconsa 200 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Tapentadol Liconsa 200 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg tapentadol (as tartrate).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Light ochre coloured, oblong and biconvex film-coated tablets, without a break-score, with a length of 18.2 mm ± 0.2 mm and a thickness of 5.6 mm ± 0.3 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This product is indicated for the management of

• severe chronic pain in adults, which can be adequately managed only with opioid analgesics.
• severe, chronic pain in children over 6 years of age and adolescents, which can be adequately managed only with opioid analgesics.

4.2 Posology and method of administration

Posology

The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient. This product should be taken twice daily, approximately every 12 hours.

Adults

Initiation of therapy

Initiation of therapy in patients currently not taking opioid analgesics Patients should start treatment with single doses of 50 mg tapentadol as prolonged-release tablet administered twice daily.

Initiation of therapy in patients currently taking opioid analgesics When switching from opioids to this product and choosing the initial dose, the nature of the previous medicinal product, administration and the mean daily dose should be taken into account. This may require higher initial doses of this product for patients currently taking opioids compared to those not having taken opioids before initiating therapy with this product

Titration and maintenance

After initiation of therapy the dose should be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician.

Experience from clinical trials has shown that a titration regimen in increments of 50 mg tapentadol as prolonged-release tablet twice daily every 3 days was appropriate to achieve adequate pain control in most of the patients.

Total daily doses of this product greater than 500 mg tapentadol have not yet been studied and are therefore not recommended.

Renal Impairment

In patients with mild or moderate renal impairment a dosage adjustment is not required (see section 5.2).

This product has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).

Hepatic Impairment

In patients with mild hepatic impairment a dosage adjustment is not required (see section 5.2).

This product should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at the lowest available dose strength, i.e. 50 mg tapentadol as prolonged-release tablet, and not be administered more frequently than once every 24 hours. At initiation of therapy a daily dose greater than 50 mg tapentadol as prolonged-release tablet is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability (see sections 4.4 and 5.2).

This product has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.4 and 5.2).

Elderly Patients (persons aged 65 years and over)

In general, a dose adaptation in elderly patients is not required. However, as elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see sections 4.2 and 5.2).

Paediatric population

Dose recommendation for children is dependent on age and body weight.

Initiation of therapy

Initiation of therapy in patients currently not taking opioid analgesics For children and adolescents from 6 years to less than 18 years, the recommended starting dose is 1.5 mg per kg body weight given every 12 hours. Nevertheless, a starting dose of 50 mg should not be exceeded. From the available tablet strengths, either 25 mg or 50 mg should be considered as starting doses.

Initiation of therapy in patients currently taking opioid analgesics When switching from opioids to this product and choosing the initial dose, the nature of the

previous medicinal product, administration and the mean daily dose should be taken into account. This may require higher initial doses of this product for patients currently taking opioids compared to those not having taken opioids before initiating therapy with this product.

Titration and maintenance

After initiation of therapy the dose should be titrated individually to a level that provides adequate analgesia and minimizes side effects under the close supervision of the prescribing physician with dose increments of 25 mg for patients less than 40 kg body weight or dose increments of 25 mg or 50 mg for patients >40 kg body weight after a minimum of 2 days since the last dose increase.

The maximum recommended dose is 3.5 mg per kg body weight given every 12 hours. The available tablet strengths should be considered to achieve the optimal dose within the general recommended dose range (1.5 mg/kg to 3.5 mg/kg), as deemed by the prescribing physician. A total dose of 500 mg per day, i.e. 250 mg given every 12 hours should not be exceeded. Individual patients have shown benefit from doses down to 1.0 mg/kg.

Renal Impairment

This product has not been studied in children and adolescents with renal impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).

Hepatic Impairment

This product has not been studied in children and adolescents with hepatic impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).

The safety and efficacy of this product in children below 6 years of age has not yet been established. Therefore this product is not recommended for use in this population.

Method of administration

This product is for oral use.

This product has to be taken whole, not divided or chewed, to ensure that the prolonged-release mechanism is maintained. This product should be taken with sufficient liquid. This product can be taken with or without food.

Treatment goals and discontinuation

Before initiating treatment with tapentadol, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with tapentadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4). Duration of treatment

Tapentadol should not be used longer than necessary

4.3 Contraindications

This product is contraindicated

• in patients with hypersensitivity to tapentadol or to any of the excipients (see section 6.1)
• in situations where active substances with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia
• in any patient who has or is suspected of having paralytic ileus
• in patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances (see section 4.5)

4.4 Special warnings and precautions for use

Tolerance and Opioid Use Disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as tapentadol. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders). Before initiating treatment with tapentadol and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician. Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with tapentadol. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months. The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate. If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Risk from concomitant use of sedating medicinal products such as benzodiazepines or related substances

Concomitant use of this product and sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe this product concomitantly with sedating medicinal products, the reduction of dose of one or both agents should be considered and the duration of the concomitant treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Respiratory Depression

At high doses or in mu-opioid receptor agonist sensitive patients, this product may produce dose-related respiratory depression. Therefore, this product should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and this product should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist-induced respiratory depression (see section 4.9).

Head Injury and Increased Intracranial Pressure

This product should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. This product should be used with caution in patients with head injury and brain tumours.

Seizures

This product has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical trials. However, like other analgesics with mu-opioid agonist activity this product should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures. In addition, tapentadol may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold (see section 4.5).

Renal Impairment

This product has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see section 4.2 and 5.2).

Hepatic Impairment

Subjects with mild and moderate hepatic impairment showed a 2-fold and 4.5-fold increase in systemic exposure, respectively, compared with subjects with normal hepatic function. this product should be used with caution in patients with moderate hepatic impairment (see section 4.2 and 5.2), especially upon initiation of treatment. This product has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.2 and 5.2).

Use in Pancreatic/Biliary Tract Disease

Active substances with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. This product should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Mixed opioid agonists/antagonists

Care should be taken when combining this product with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine). In patients maintained on buprenorphine for the treatment of opioid dependence, alternative treatment options (like e.g. temporary buprenorphine discontinuation) should be considered, if administration of full mu-agonists (like tapentadol) becomes necessary in acute pain situations. On combined use with buprenorphine, higher dose requirements for full mu-receptor agonists have been reported and close monitoring of adverse events such as respiratory depression is required in such circumstances.

Paediatric population

The same warnings and precautions for use of this product apply for children, with following additional considerations:

This product has not been studied in children aged below 6 years (see section 4.1 and 4.2) therefore the use in this population is not recommended.

This product has not been systematically evaluated in children and adolescents with obesity, therefore, paediatric patients with obesity should be extensively monitored and the recommended maximum dose should not be exceeded.

This product has not been studied in children and adolescents with renal or hepatic impairment, therefore the use in this population is not recommended (see sections 4.2 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

Centrally-acting medicinal products/central nervous system (CNS) depressants, including alcohol and CNS depressant narcotic drugs Sedative medicines such as benzodiazepines or related drugs

The concomitant use of this product with sedating medicinal products such as benzodiazepines or other respiratory or CNS depressants (other opioids, antitussives or substitution treatments, barbiturates, antipsychotics, H1-antihistamines, alcohol) increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Therefore, when a combined therapy of this product with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered and the duration of the concomitant use should be limited (see section 4.4). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.

Mixed opioid agonists/antagonists

Care should be taken when combining this product with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) (see also section 4.4).

This product can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions.

There have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.

Serotonin syndrome is likely when one of the following is observed:

• Spontaneous clonus
• Inducible or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature > 38°C and inducible ocular clonus.

Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

The major elimination pathway for tapentadol is conjugation with glucuronic acid mediated via uridine diphosphate transferase (UGT) mainly UGT1A6, UGT1A9 and UGT2B7 isoforms. Thus, concomitant administration with strong inhibitors of these isoenzymes (e.g. ketoconazole, fluconazole, meclofenamic acid) may lead to increased systemic exposure of tapentadol (see section 5.2).

For patients on tapentadol treatment, caution should be exercised if concomitant drug administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort (hypericum perforatum)) starts or stops, since this may lead to decreased efficacy or risk for adverse effects, respectively.

Treatment with this product should be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis (see section 4.4).

Concomitant administration of tapentadol with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is very limited amount of data from the use in pregnant women. Studies in animals have not shown teratogenic effects. However, delayed development and embryotoxicity were observed at doses resulting in exaggerated pharmacology (mu-opioid-related CNS effects related to dosing above the therapeutic range). Effects on the postnatal development were already observed at the maternal NOAEL (see section 5.3).

This product should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Labour and Delivery

The effect of tapentadol on labour and delivery in humans is unknown. This product is not recommended for use in women during and immediately before labour and delivery.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Due to the mu-opioid receptor agonist activity of tapentadol, new-born infants whose mothers have been taking tapentadol should be monitored for respiratory depression.

Breast feeding

There is no information on the excretion of tapentadol in human milk. From a study in rat pups suckled by dams dosed with tapentadol it was concluded that tapentadol is excreted via milk (see section 5.3). Administration to nursing women is not recommended as tapentadol may be secreted

in breast milk and may cause respiratory depression in the infant. Therefore, a risk to the suckling child cannot be excluded. This product should not be used during breast feeding.

Fertility

No human data on the effect of tapentadol on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

This product may have major influence on the ability to drive and use machines due to the fact that it may adversely affect central nervous system functions (see section 4.8). This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilisers (see section 4.4). Patients should be cautioned as to whether driving or use of machines is permitted.

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:

1. 1. The medicine is likely to affect your ability to drive
2. 2. Do not drive until you know how the medicine affects you
3. 3. It is an offence to drive while under the influence of this medicine
4. 4.

   However, you would not be committing an offence (called ‘statutory defence’) if:

   • The medicine has been prescribed to treat a medical or dental problem and
   • You have taken it according to the instructions given by the prescriber and in the information
   • provided with the medicine and
   • It was not affecting your ability to drive safely

4.8 Undesirable effects

The adverse drug reactions that were experienced by patients in the placebo controlled trials performed with this product were predominantly of mild and moderate severity. The most frequent adverse drug reactions were in the gastrointestinal and central nervous system (nausea, dizziness, constipation, headache and somnolence).

The table below lists adverse drug reactions that were identified from clinical trials performed with tapentadol prolonged-release products. They are listed by class and frequency. Frequencies are defined as 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 (cannot be estimated from the available data).

* Post-marketing rare events of angioedema, anaphylaxis and anaphylactic shock have been reported.

** Post marketing cases of delirium were observed in patients with additional risk factors such as cancer and advanced age.

Clinical trials performed with tapentadol prolonged-release tablets with patient exposure up to 1 year have shown little evidence of withdrawal symptoms upon abrupt discontinuations and these were generally classified as mild, when they occurred. Nevertheless, physicians should be vigilant for symptoms of withdrawal (see section 4.2) and treat patients accordingly should they occur.

The risk of suicidal ideation and suicides committed is known to be higher in patients suffering from chronic pain. In addition, substances with a pronounced influence on the monoaminergic system have been associated with an increased risk of suicidality in patients suffering from depression, especially at the beginning of treatment. For tapentadol data from clinical trials and post-marketing reports do not provide evidence for an increased risk.

Drug dependence

Repeated use of tapentadol can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Paediatric population

Frequency, type and severity of adverse reactions in children and adolescents treated with this product are expected to be the same as in adults treated with this product. No new safety issues have been identified from completed paediatric trial for any of the age subgroups investigated. Limited clinical trial data on withdrawal symptoms in children using PR formulation of tapentadol are available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms

Human experience with overdose of tapentadol is limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid receptor agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms include, referring to the clinical setting, in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest that may be fatal. Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Management

Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of tapentadol is suspected.

Pure opioid receptor antagonists such as naloxone are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid receptor antagonist. Administration of an opioid receptor antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid receptor antagonists is suboptimal or only brief in nature, an additional dose of antagonist (e.g. naloxone) should be administered as directed by the manufacturer of the product. Gastrointestinal decontamination may be considered in order to eliminate unabsorbed active substance. Gastrointestinal decontamination with activated charcoal or by gastric lavage may be considered within 2 hours after intake. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; opioids; other opioids ATC code: N02AX06

Tapentadol is a strong analgesic with μ-agonistic opioid and additional noradrenaline reuptake inhibition properties. Tapentadol exerts its analgesic effects directly without a pharmacologically active metabolite.

Tapentadol demonstrated efficacy in preclinical models of nociceptive, neuropathic, visceral and other pain. Efficacy has been verified in clinical trials with tapentadol prolonged-release tablets in nociceptive and neuropathic chronic pain conditions. The trials in pain due to chronic low back pain showed similar analgesic efficacy of tapentadol to a strong opioid used as a comparator.

Effects on the cardiovascular system: In a thorough human QT trial, no effect of multiple therapeutic and supratherapeutic doses of tapentadol on the QT interval was shown. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Paediatric population

The extension of the indication to children > 6 years of age is based on an exposure-matching extrapolation approach supported by popPK model simulations. With the recommended doses in children, similar tapentadol exposure is reach as in adults.

One randomized, active-controlled, open-label non-inferiority study (KF5503/66) has been performed in 69 children aged 6 to less than 18 years old suffering from severe pain that was expected to require opioid treatment for a minimum of 14 days. 45 of these children were randomized to tapentadol PR. Children were treated with weight adjusted doses between 25 mg and 250 mg tapentadol PR twice daily or equivalent doses of the comparator drug during a 14-days treatment period. The safety profile of tapentadol PR in these children was comparable to the comparator drug and similar to the safety profile observed in adults treated with tapentadol PR. The safety profile of tapentadol PR was maintained in 9 children during an open label extension period of up to one year.

Post-marketing data

Two post-marketing studies were performed to address the practical use of tapentadol.

The efficacy of tapentadol prolonged-release tablets has been verified in a multicenter, randomized, double blind parallel-group trial with patients suffering from low back pain with a neuropathic component (KF5503/58). Reductions in average pain intensity were similar in the tapentadol treatment group and the comparator treatment group i.e. receiving a combination of tapentadol prolonged-release tablets and pregabalin immediate release tablets. In an open-label, multicenter, randomized trial with patients having severe chronic low back pain with a neuropathic component (KF5503/60), tapentadol prolonged-release tablets were associated with significant reductions in average pain intensity.

5.2 Pharmacokinetic properties

Absorption

Mean absolute bioavailability after single-dose administration (fasting) of tapentadol is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are observed at between 3 and 6 hours after administration of prolonged-release tablets.

Dose proportional increases for AUC (the most relevant exposure parameter for prolonged-release formulations) have been observed after administration of the prolonged-release tablets over the therapeutic dose range. A multiple dose trial with twice daily dosing using 86 mg and 172 mg tapentadol administered as prolonged-release tablets showed an accumulation ratio of about 1.5 for the parent active substance which is primarily determined by the dosing interval and apparent half-life of tapentadol.

Food Effect

The AUC and C_max increased by 8% and 18%, respectively, when prolonged-release tablets were administered after a high-fat, high-calorie breakfast. This was judged to be without clinical relevance as it falls into the normal inter-subject variability of tapentadol PK parameters. This product may be given with or without food.

Distribution

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (V_z) for tapentadol is 540 +/- 98 l. The serum protein binding is low and amounts to approximately 20%.

Metabolism

In humans, the metabolism of tapentadol is extensive. About 97% of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% of the dose is excreted in urine as conjugated forms (55% glucuronide and 15% sulfate of tapentadol). Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3% of active substance is excreted in urine as unchanged active substance. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolised by conjugation. Therefore, active substance metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation.

None of the metabolites contributes to the analgesic activity.

Elimination

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 ml/min.

Special populations

Elderly patients

The mean exposure (AUC) to tapentadol was similar in a trial with elderly subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean C_max observed in the elderly subject group compared to young adult subjects.

Renal Impairment

AUC and C_max of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.

Hepatic Impairment

Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for C_max; and 1.2 and 1.4, respectively, for t_1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Pharmacokinetic Interactions

Tapentadol is mainly metabolised by Phase 2 glucuronidation, and only a small amount is metabolised by Phase 1 oxidative pathways. As glucuronidation is a high capacity/low affinity system, which is not easily saturated even in disease, and as therapeutic concentrations of active substances are generally well below the concentrations needed for potential inhibition of glucuronidation, any clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. In a set of drug-drug interaction trials using paracetamol, naproxen, acetylsalicylic acid and probenecid, a possible influence of these active substances on the glucuronidation of tapentadol was investigated. The trials with probe active substances naproxen (500 mg twice daily for 2 days) and probenecid (500 mg twice daily for 2 days) showed increases in AUC of tapentadol by 17% and 57%, respectively. Overall, no clinically relevant effects on the serum concentrations of tapentadol were observed in these trials.

Furthermore, interaction trials of tapentadol with metoclopramide and omeprazole were conducted to investigate a possible influence of these active substances on the absorption of tapentadol. These trials also showed no clinically relevant effects on tapentadol serum concentrations. In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.

Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

Paediatric population

Absorption

Using weight adjusted dosing, mean serum concentrations of tapentadol observed in the paediatric population were in the range of concentrations observed in adult subjects.

Food Effect

A dedicated food effect trial has not been performed in children and adolescents. In the phase II/III trial performed in children and adolescents tapentadol was given irrespective of food intake. Based on efficacy data obtained during the trial in children and adolescents, the food effect does not appear to be of clinical relevance. Tapentadol may be given with or without food.

Distribution

Based on a population pharmacokinetic analysis, the mean (± SD) apparent volume of distribution (V/F) of tapentadol following oral administration of tapentadol PR tablets in paediatrics was 528 L (± 227 L) for children aged 6 years to less than 12 years, and 795 L (± 220 L) for children aged 12 years to less than 18 years.

Biotransformation

In humans aged 5 months or above the metabolism of tapentadol is extensive.

Elimination

Based on a population pharmacokinetic analysis, the mean (± SD) apparent oral clearance (CL/F) of tapentadol following oral administration of tapentadol PR tablets in paediatrics was 135 L/h (± 51 L/h) for children aged 6 years to less than 12 years, and 180 L/h (± 45 L/h) for children aged 12 years to less than 18 years.

Special populations

Renal and Hepatic Impairment

Tapentadol has not been studied in children and adolescents with renal and hepatic impairment.

Pharmacokinetic Interactions

Dedicated drug-drug interaction trials have not been performed in children and adolescents.

5.3 Preclinical safety data

Tapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an in vitro chromosomal aberration test, but when the test was repeated the results were clearly negative. Tapentadol was not genotoxic in vivo, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Long-term animal studies did not identify a potential carcinogenic risk relevant to humans.

Tapentadol had no influence on male or female fertility in rats but there was reduced in utero survival at the high dose. It is not known whether this was mediated via the male or the female. Tapentadol showed no teratogenic effects in rats and rabbits following intravenous and subcutaneous exposure; however, delayed development and embryotoxicity were observed after administration of doses resulting in exaggerated pharmacology. After intravenous dosing in rats reduced in utero survival was seen. In rats tapentadol caused increased mortality of the F1 pups that were directly exposed via milk between days 1 and 4 post partum already at dosages that did not provoke maternal toxicities. There were no effects on neurobehavioural parameters.

Excretion into breast milk was investigated in rat pups suckled by dams dosed with tapentadol. Pups were dose-dependently exposed to tapentadol and tapentadol O-glucuronide. It is concluded that tapentadol is excreted via milk. Juvenile rats were treated from post-natal day 6 to day 90, which covered the period of development corresponding to infancy, childhood and adolescence in humans. During the first 3 days of treatment, a numerically higher incidence of mortality was observed at doses of ≥ 25 mg/kg/day with Tapentadol plasma exposure at the lowest observed adverse effect level (LOAEL) comparable to the predicted clinical plasma exposure in children. Tapentadol was well tolerated in pups older than 10 days. There were no treatment-related clinical signs, effects on body weight, food consumption, pre-weaning or reproductive development, long-bone growth, motor activity, behaviour or learning and memory. Organ weights and macroscopic or microscopic evaluation showed no treatment-related changes. Tapentadol did not influence sexual development, mating or pregnancy parameters in the treated animals.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Povidone K30

Microcrystalline cellulose

Hypromellose

Colloidal anhydrous silica

Magnesium stearate

Tablet coat:

Hypromellose (E464)

Polydextrose (E1200)

Titanium dioxide (E171)

Maltodextrin

Medium-chain triglycerides

Yellow iron oxide (E172)

Red iron oxide (E172).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVdC/PVC-aluminium blister

Packs with 7, 10, 14, 20, 24, 28, 30, 40, 50, 54, 56, 60, 90 and 100 prolonged-release tablets.

PVC/PVdC/PVC- aluminium perforated unit-dose blister Packs with 7x1, 10 x1, 14 x1, 20 x1, 24 x1, 28 x1, 30 x1, 40 x1, 50 x1, 54 x1, 56 x1, 60 x1, 90 x1 and 100 x1 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements

7 MARKETING AUTHORISATION HOLDER

Laboratorios Liconsa, S.A. C/Dulcinea S/N, 28805 Alcalá de Henares, Madrid, Spain

8 MARKETING AUTHORISATION NUMBER(S)

PL 23218/0232

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

13/11/2023

10 DATE OF REVISION OF THE TEXT

05/12/2025