Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, United Kingdom
PALEXIA is contraindicated:
PALEXIA has a potential for abuse and addiction. This should be considered when prescribing or dispensing PALEXIA in situations where there is concern about an increased risk of misuse, abuse, addiction, or diversion.
All patients treated with active substances that have mu-opioid receptor agonist activity should be carefully monitored for signs of abuse and addiction.
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).
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).
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 tumors.
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).
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).
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).
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.
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 propylene glycol and sodium
This medicine contains 10 mg propylene glycol per 5 ml solution (maximum single dose) which is equivalent to 2.0 mg/ml.
This medicine contains less than 1 mmol sodium (23 mg) per maximum single dose, that is to say essentially ‘sodium-free’.
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. Thus, no long-term safety data in children (e.g. for growth or development) are available.
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).
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:
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.
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) .
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.
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.
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.
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.
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).
Adverse drug reactions:
Rare: Drug hypersensitivity*
Common: Decreased appetite
Common: Anxiety, Confusional state, Hallucination, Sleep disorder, Abnormal dreams
Uncommon: Depressed mood, Disorientation, Agitation, Nervousness, Restlessness, Euphoric mood
Rare: Thinking abnormal
Unknown: Delirium**
Very common: Dizziness, Somnolence, Headache
Common: Tremor
Uncommon: Disturbance in attention, Memory impairment, Presyncope, Sedation, Ataxia, Dysarthria, Hypoaesthesia, Paraesthesia, Muscle contractions involuntary
Rare: Convulsion, Depressed level of consciousness, Coordination abnormal
Uncommon: Visual disturbance
Uncommon: Heart rate increased, Palpitations
Rare: Heart rate decreased
Common: Flushing
Uncommon: Blood pressure decreased
Uncommon: Respiratory depression, Oxygen saturation decreased, Dyspnoea
Very common: Nausea, Vomiting
Common: Constipation, Diarrhoea, Dyspepsia, Dry mouth
Uncommon: Abdominal discomfort
Rare: Impaired gastric emptying
Common: Pruritus, Hyperhidrosis, Rash
Uncommon: Urticaria
Common: Muscle spasms
Uncommon: Sensation of heaviness
Uncommon: Urinary hesitation, Pollakiuria
Common: Asthenia, Fatigue, Feeling of body temperature change
Uncommon: Drug withdrawal syndrome, Oedema, Feeling abnormal, Feeling drunk, Irritability, 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 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.
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 for any of the age subgroups investigated.
No clinical trial data on withdrawal symptoms in children using IR formulation 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 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.
Not applicable.
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