4.1. Therapeutic indications

PALEXIA SR 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 above 6 years and adolescents, which can be adequately managed only with opioid analgesics.

4.2. Posology and method of administration

Treatment goals and discontinuation

Before initiating treatment with PALEXIA SR, 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 SR, 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).

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.

PALEXIA SR should be taken twice daily, approximately every 12 hours.

Duration of treatment

PALEXIA SR should not be used longer than necessary.

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 PALEXIA SR 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 PALEXIA SR for patients currently taking opioids compared to those not having taken opioids before initiating therapy with PALEXIA SR.

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 PALEXIA SR greater than 500 mg tapentadol have not yet been studied and are therefore not recommended.

Special Population

Renal Impairment

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

PALEXIA SR 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 SR 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).

PALEXIA SR 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 PALEXIA SR 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 PALEXIA SR for patients currently taking opioids compared to those not having taken opioids before initiating therapy with PALEXIA SR.

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

PALEXIA SR 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 SR 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 PALEXIA SR in children below 6 years of age has not yet been established. Therefore PALEXIA SR is not recommended for use in this population.

Method of administration

PALEXIA SR is for oral use.

The tablet has to be taken whole, not divided or chewed, to ensure that the prolonged-release mechanism is maintained. PALEXIA SR should be taken with sufficient liquid.

PALEXIA SR can be taken with or without food.

The shell (matrix) of the tapentadol tablet may not be digested completely and therefore it can be eliminated and seen in the patient's stool. However, this finding has no clinical relevance, since the active substance of the tablet will have already been absorbed.

4.3. Contraindications

PALEXIA SR 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)

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 PALEXIA SR. 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 SR 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.

Physicians should be vigilant for symptoms of withdrawal after repeated administration of tapentadol and avoid abrupt cessation (see section 4.2 and section 4.8).

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

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

Post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI)

Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).

If opioids are required for post-operative pain, then the immediate release opioids are preferred for short-term treatment. In patients who are treated with prolonged-release opioids prior to surgery, treatment should be reviewed.

Head Injury and Increased Intracranial Pressure

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

Seizures

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

PALEXIA SR 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 SR 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 SR 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 SR prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.

Paediatric population

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

PALEXIA SR 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.

PALEXIA SR 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.

PALEXIA SR 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

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

PALEXIA SR 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 PALEXIA SR 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 SR 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).

PALEXIA SR 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 SR 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 SR should not be used during breast feeding.

Fertility

No human data on the effect of PALEXIA SR 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

PALEXIA SR 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 change 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.

4.8. Undesirable effects

The adverse drug reactions that were experienced by patients in the placebo controlled trials performed with PALEXIA SR 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 PALEXIA SR and from post-marketing environment. 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).

ADVERSE DRUG REACTIONS

System Organ Class

Frequency

Very common

Common

Uncommon

Rare

Unknown

Immune system disorders

Drug hypersensitivity*

Metabolism and nutrition disorders

Decreased appetite

Weight decreased

Psychiatric disorders

Anxiety, Depressed mood, Sleep disorder, Nervousness, Restlessness

Disorientation, Confusional state, Agitation, Perception disturbances, Abnormal dreams, Euphoric mood

Drug dependence, Thinking abnormal

Delirium**

Nervous system disorders

Dizziness, Somnolence, Headache

Disturbance in attention, Tremor, Muscle contractions involuntary

Depressed level of consciousness, Memory impairment, Mental impairment, Syncope, Sedation, Balance disorder, Dysarthria, Hypoaesthesia, Paraesthesia

Convulsion, Presyncope, Coordination abnormal

Eye disorders

Visual disturbance

Cardiac disorders

Heart rate increased, Heart rate decreased, Palpitations

Vascular disorders

Flushing

Blood pressure decreased

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Respiratory depression

Gastrointestinal disorders

Nausea, Constipation

Vomiting, Diarrhoea, Dyspepsia

Abdominal discomfort

Impaired gastric emptying

Skin and subcutaneous tissue disorders

Pruritus, Hyperhidrosis, Rash

Urticaria

Renal and urinary disorders

Urinary hesitation, Pollakiuria

Reproductive system and breast disorders

Sexual dysfunction

General disorders and administration site conditions

Asthenia, Fatigue, Feeling of body temperature change, Mucosal dryness, Oedema

Drug withdrawal syndrome, Feeling abnormal, Irritability

Feeling drunk, Feeling of relaxation

* 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 PALEXIA SR 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 PALEXIA SR 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).

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.

Paediatric population

Frequency, type and severity of adverse reactions in children and adolescents treated with PALEXIA SR are expected to be the same as in adults treated with PALEXIA SR. 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.

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.

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.