- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Duration of treatmentThe oral solution is intended for acute pain situations. If longer term treatment is anticipated or becomes necessary 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 tablets should be considered. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. Calculation table for PALEXIA 20 mg/ml oral solution:
|Single dose of tapentadol to be prescribed||Volume (ml) to be administered|
|25 mg||1.25 ml|
|50 mg||2.5 ml|
|75 mg||3.75 ml|
|100 mg||5 ml|
Discontinuation of treatmentWithdrawal symptoms could occur after abrupt discontinuation of treatment with tapentadol (see section 4.8). When a patient no longer requires therapy with tapentadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
Renal ImpairmentIn 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 ImpairmentIn 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).
Older People (persons aged 65 years and over)In general, a dose adaptation in older people is not required. However, as older people 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 PatientsThe safety and efficacy of PALEXIA in children and adolescents below 18 years of age has not yet been established. Therefore PALEXIA is not recommended for use in this population.
Method of administrationPALEXIA can be taken with or without food. PALEXIA oral solution can be taken either undiluted or diluted in water or any non-alcoholic drink. There is an oral syringe 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 can be taken via enteral tubes, e.g. nasogastric or percutaneous endoscopic gastrostomy (PEG) tubes.
Potential for Abuse and Addiction/ Dependence SyndromePALEXIA 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.
Respiratory DepressionAt 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 PressurePALEXIA 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.
SeizuresPALEXIA 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.
Renal ImpairmentPALEXIA 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 ImpairmentSubjects 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 DiseaseActive 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.
Mixed opioid agonists/antagonistsCare 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.
Mixed opioid agonists/antagonistsCare 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).In isolated cases 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). Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. 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 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 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.
PregnancyThere 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.
Labour and DeliveryThe 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.
LactationThere 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.
|ADVERSE DRUG REACTIONS|
|System Organ Class||Frequency|
|Immune system disorders||Drug hypersensitivity*|
|Metabolism and nutrition disorders||Decreased appetite|
|Psychiatric disorders||Anxiety, Confusional state, Hallucination, Sleep disorder, Abnormal dreams||Depressed mood, Disorientation, Agitation, Nervousness, Restlessness, Euphoric mood||Thinking abnormal|
|Nervous system disorders||Dizziness, Somnolence, Headache||Tremor||Disturbance in attention, Memory impairment, Presyncope, Sedation, Ataxia, Dysarthria, Hypoaesthesia, Paraesthesia, Muscle contractions involuntary||Convulsion, Depressed level of consciousness, Coordination abnormal|
|Eye disorders||Visual disturbance|
|Cardiac disorders||Heart rate increased, Palpitations||Heart rate decreased|
|Vascular disorders||Flushing||Blood pressure decreased|
|Respiratory, thoracic and mediastinal disorders||Respiratory depression, Oxygen saturation decreased, Dyspnoea|
|Gastrointestinal disorders||Nausea, Vomiting||Constipation, Diarrhoea, Dyspepsia, Dry mouth||Abdominal discomfort||Impaired gastric emptying|
|Skin and subcutaneous tissue disorders||Pruritus, Hyperhidrosis, Rash||Urticaria|
|Musculoskeletal and connective tissue disorder||Muscle spasms||Sensation of heaviness|
|Renal and urinary disorders||Urinary hesitation, Pollakiuria|
|General disorders and administration site conditions||Asthenia, Fatigue, Feeling of body temperature change||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.|
Reporting of suspected adverse reactionsReporting 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.
SymptomsHuman experience with overdose of tapentadol is very 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.
ManagementManagement 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.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with PALEXIA in all subsets of the paediatric population in moderate to severe acute pain (see section 4.2 for information on paediatric use).
AbsorptionTapentadol 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 Cmax 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 EffectThe AUC and Cmax 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 trials, the food effect does not appear to be of clinical relevance PALEXIA may be given with or without food.
DistributionTapentadol 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%.
MetabolismIn 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.
EliminationTapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The total clearance after intravenous administration is 1530 +/- 177 ml/min. Terminal half-life is on average 4 hours after oral administration.
Older peopleThe mean exposure (AUC) to tapentadol was similar in a trial with older subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean Cmax observed in the older subject group compared to young adult subjects.
Renal ImpairmentAUC and Cmax 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 ImpairmentAdministration 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 Cmax; and 1.2 and 1.4, respectively, for t1/2.The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.
Pharmacokinetic InteractionsTapentadol 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.
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