Palexia 20 mg/ml Oral Solution

PALEXIA is indicated for the relief of moderate to severe acute pain in children and adolescents from 2 years of age with a body weight of more than 16 kg and in adults, which can be adequately managed only with opioid analgesics.

The use of PALEXIA in children is restricted to hospital use where appropriate equipment to enable respiratory support is available.

Treatment goals and discontinuation

Before initiating treatment with PALEXIA, 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 PALEXIA, 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).

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.

Adults:

Patients should start treatment with single doses of 50 mg tapentadol as oral solution administered every 4 to 6 hours. Higher starting doses may be necessary depending on the pain intensity and the patient's previous history of analgesic requirements.

On the first day of dosing, an additional dose may be taken as soon as one hour after the initial dose, if pain control is not achieved. The dose should then be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician.

Total daily doses greater than 700 mg tapentadol on the first day of treatment and maintenance daily doses greater than 600 mg tapentadol have not been studied and are therefore not recommended.

Calculation table for PALEXIA 20 mg/ml oral solution:

Duration of treatment

The oral solution is intended for acute pain situations. If longer term treatment is anticipated or becomes necessary in adults and effective pain relief in the absence of intolerable adverse events was achieved with PALEXIA, the possibility of switching the patient to therapy with PALEXIA prolonged release formulation should be considered. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis.

PALEXIA should not be used longer than necessary.

Special populations

Renal Impairment

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

PALEXIA 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).

PALEXIA should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at 25 mg tapentadol as oral solution and not be administered more frequently than once every 8 hours. At initiation of therapy a daily dose greater than 150 mg tapentadol is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval (see sections 4.4 and 5.2).

PALEXIA 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.

For children and adolescents from 2 years to less than 18 years of age the recommended single dose is 1.25 mg per kg body weight every 4 hours.

The maximum dose per day is 7.5 mg per kg body weight (≙ 6 x single dose).

The maximum dose for children and adolescents with a high BMI (body mass index) must not exceed the calculated maximum dose for a body weight at the 97.5 percentile for the given age.

Dose reductions may be considered over time as acute pain decreases.

Dose recommendation for children with a body weight of more than 16 kg (PALEXIA 20 mg/ml oral solution)

PALEXIA 20 mg/ml is not recommended for children with a body weight of 16 kg or less due to the high concentration of tapentadol.

The safety and efficacy of PALEXIA in children younger than 2 years have not yet been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made for children younger than 2 years.

Duration of treatment

The oral solution is intended for acute pain situations. As with all symptomatic treatments, the continued use of tapentadol exceeding 3 days must be evaluated on an ongoing basis.

PALEXIA should not be used longer than necessary.

Renal Impairment

PALEXIA 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

PALEXIA 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).

Method of administration

PALEXIA is for oral use.

PALEXIA can be taken with or without food.

PALEXIA can be taken either undiluted or diluted in water or any non-alcoholic drink. There is a dosing pipette with an attached adaptor in the pack which is recommended to be used to take the exact volume needed from the bottle corresponding to the prescribed single dose of tapentadol.

PALEXIA may be administered through a nasogastric tube made of polyurethane, silicone, or polyvinyl chloride (these materials were tested and showed no interactions or degradation of tapentadol).

PALEXIA is contraindicated

• in patients with hypersensitivity to tapentadol or to any of the excipients listed in 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)

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 PALEXIA. 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 PALEXIA 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.

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

Concomitant use of PALEXIA 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 PALEXIA 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, PALEXIA may produce dose-related respiratory depression. Therefore, PALEXIA should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and PALEXIA 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

PALEXIA 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. PALEXIA should be used with caution in patients with head injury and brain tumours.

Seizures

PALEXIA 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 PALEXIA is not recommended 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

PALEXIA 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. PALEXIA should be used with caution in patients with moderate hepatic impairment (see section 4.2 and 5.2), especially upon initiation of treatment.

PALEXIA 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. PALEXIA 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 apnea (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 PALEXIA 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.

PALEXIA 20 mg/ml contains sodium benzoate, propylene glycol and sodium

This medicine contains 5.9 mg sodium benzoate in 5 ml solution (maximum single dose) which is equivalent to 1.18 mg/ml. Benzoate salt may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicine contains 10 mg propylene glycol per 5 ml solution (maximum single dose) which is equivalent to 2 mg/ml.

This medicine contains less than 1 mmol sodium (23 mg) per maximum single dose, that is to say essentially 'sodium-free'.

Paediatric population

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

PALEXIA 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).

PALEXIA is not recommended in children aged below 2 years (see section 4.1)

PALEXIA is not recommended in children with a body weight of 16 kg or less (see section 4.2)

PALEXIA has not been systematically evaluated in children and adolescent with obesity, therefore, paediatric patients with obesity should be extensively monitored and the recommended maximum dose for the age should not be exceeded.

PALEXIA is intended for use in acute pain, and was therefore investigated in short-term treatment. No long-term safety data in children are available for PALEXIA.

Centrally-acting medicinal products/central nervous system (CNS) depressants, including alcohol and CNS depressant narcotic drugs

The concomitant use of PALEXIA 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 PALEXIA 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 PALEXIA with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) (see also section 4.4).

PALEXIA 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).

Due to the major elimination pathway being glucuronide conjugation the potential for interactions in adults is low.

Additionally, in vitro, tapentadol was found not to induce or inhibit any of the main CYP enzymes, including CYP3A4.

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 PALEXIA 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.

Concomitant administration of PALEXIA 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.

Paediatric population

Due to the major elimination pathway being glucuronide conjugation the potential for interactions in children aged more than 5 months is low (see section 4,2) .

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).

PALEXIA should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Long-term maternal use of opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NOWS). Neonatal opioid withdrawal syndrome can be life-threatening if not recognized and treated. An antidote for the newborn should be readily available.

Labour and Delivery

The effect of tapentadol on labour and delivery in humans is unknown. PALEXIA is not recommended for use in women during and immediately before labour and delivery. 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 in milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. PALEXIA should not be used during breast feeding.

Fertility

No human data on the effect of PALEXIA 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).

PALEXIA may have major influence on the ability to drive and use machines, because it may adversely affect central nervous system functions (see section 4.8). This has to be expected especially at the beginning of treatment, when any changes of dosage occur as well as in connection with the use of 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. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive if you are unfit to drive

• 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.

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

The most severe adverse drug reactions are sedation, respiratory depression and allergic reactions.

The table below lists adverse drug reactions that were identified from clinical trials performed in adults with another immediate release formulation of tapentadol (PALEXIA film-coated tablets) and from post-marketing data in adults. They are listed by class and frequency. Frequencies are defined as very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Clinical trials performed in adults using another immediate release formulation of tapentadol (PALEXIA film-coated tablets) with patient exposure up to 90 days 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 PALEXIA 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 PALEXIA are expected to be the same as in adults treated with PALEXIA. No new safety issues have been identified from completed paediatric trials in acute pain for any of the age subgroups investigated.

No clinical trial data on withdrawal symptoms in children using the oral solution of tapentadol are available; however physicians should be vigilant for symptoms of withdrawal after repeated administration of tapentadol and its abrupt cessation (see section 4.2).

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.

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 .

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.

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 inflammatory pain; Efficacy has been verified in clinical trials in adults with another immediate-release formulation of tapentadol (film-coated tablets) covering nociceptive pain conditions including postoperative orthopaedic and abdominal pain as well as chronic pain due to osteoarthritis of the hip or knee. In general the analgesic effect of tapentadol in nociceptive pain trials in adults was similar to that observed with a strong opioid used as comparator.

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

Paediatric population

Efficacy of tapentadol oral solution taken for up to 72 hours has been demonstrated in children and adolescents (age between 2 years and less than 18 years of age) with postsurgical pain.

The bioavailability as assessed by C_maxand AUC and all other pharmacokinetic parameters determined for tapentadol after administration of 100 mg tapentadol as oral solution were similar compared to a 100 mg film-coated tablet (another oral immediate-release formulation). Therefore the information given below based on trials with film-coated tablets is also applicable to the oral solution.

Absorption

Tapentadol is rapidly and completely absorbed after oral administration of PALEXIA. Mean absolute bioavailability after single-dose administration (fasting) is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after administration of film-coated tablets. Dose-proportional increases in the C_max and AUC values of tapentadol have been observed after administration of film-coated tablets over the oral therapeutic dose range.

A multiple (every 6 hour) dose trial with doses ranging from 75 to 175 mg tapentadol administered as film-coated tablets showed an accumulation ratio between 1.4 and 1.7 for the parent active substance and between 1.7 and 2.0 for the major metabolite tapentadol‑O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite. Steady state serum concentrations of tapentadol are reached on the second day of the treatment regimen.

Food Effect

The AUC and C_max increased by 25% and 16%, respectively, when film-coated tablets were administered after a high-fat, high-calorie breakfast. The time to maximum plasma concentration was delayed by 1.5 hours under these conditions. Based on efficacy data obtained at early assessment time points during phase II/III, the food effect does not appear to be of clinical relevance PALEXIA may be given with or without food.

Distribution

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 l.

The serum protein binding is low and amounts to approximately 20% mainly bound to albumin.

Metabolism

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 glucoronidation.

None of the metabolites contributes to the analgesic activity.

Elimination

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The total clearance after intravenous administration 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 glucuronidation, and only a small amount is metabolised by 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 glucoronidation 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

In the paediatric population the maximum serum concentrations were observed at a similar time to adults, with no age related changes.

A multiple dose trial with PALEXIA given every 4h as per dosing recommendation (see section 4.2) to children aged 2 years to less than 7 years showed serum concentrations of tapentadol within the range of concentrations observed in adult subjects. The observed tapentadol concentrations were also within the predicted concentration range from a population pharmacokinetic (popPK) model based on single dose PK data, confirming the linear and predictable PK of tapentadol. Accumulation in paediatric subjects (accumulation ratio 1.7 for tapentadol) was in the range observed for adults.

Food Effect

A dedicated food effect trial has not been performed in children and adolescents. In the phase III trial performed in children and adolescents tapentadol oral solution was given irrespective of food intake.

Based on efficacy data obtained during the phase III trial in children and adolescents, the food effect does not appear to be of clinical relevance. PALEXIA may be given with or without food.

Distribution

The volume of distribution per age group in children following oral administration of tapentadol and derived from popPK analysis is shown in the following table:

Parameters based on the final tapentadol paediatric popPK model

Metabolism

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

Elimination

The paediatric clearance of tapentadol following oral administration and derived from PopPK analysis for the different age groups is shown in the table below.

Parameters based on the final tapentadol paediatric popPK model

Special populations

Renal and Hepatic Impairment

PALEXIA 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.

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 (mu-opioid related CNS effects related to dosing above the therapeutic range). 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 neurobehavioral 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 was concluded that tapentadol is excreted in 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 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.

Sodium benzoate (E 211)

Citric acid monohydrate

Sucralose (E 955)

Raspberry flavor, containing propylene glycol (E 1520)

Sodium hydroxide (for pH adjustment)

Purified water

Not applicable

5 years

After first opening of the bottle, the solution should not be used for longer than six weeks.

Unopened: This medicinal product does not require any special storage conditions.

After first opening: Store in an upright position.

High density polyethylene (HDPE)-bottles sealed with aluminium foil liner and closed with a high density polyethylene (HDPE) / polypropylene (PP) child-resistant cap.

Each bottle of the oral solution is provided with a dosing pipette and an adapter attached to the dosing pipette.

The scale of the 5 ml dosing pipette is subdivided in 0.1 ml intervals. Additionally, the right scale shows the single doses for adults.

100 ml bottles and 200 ml bottles

Not all pack sizes may be marketed.

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

For other handling see section 4.2