PALEXIA

1ml oral solution contains 4mg tapentadol (as hydrochloride)

Oral solution

Clear, colourless solution

pH 3.5 to 4.5

PALEXIA is indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics.

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.

Patients should start treatment with single doses of 50mg 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 dailydoses greater than 700mg tapentadol on the first day of treatment and maintenance daily doses greater than 600mg tapentadol have not been studied and are therefore not recommended.

Duration of treatment

The oral solution is intended for acute pain siuations. 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 4mg/ml oral solution:

Discontinuation of treatment

Withdrawal 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 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 25mg tapentadol as oral solution and not be administered more frequently than once every 8 hours. At initiation of therapy a daily dose greater than 150mg 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 Patients

The 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 administration

PALEXIA 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.

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)

Potential for Abuse and Addiction/ Dependence Syndrome

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.

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 tumors.

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.

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.

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.

Medicinal products like benzodiazepines, barbiturates and opioids (analgesics, antitussives or substitution treatments) may enhance the risk of respiratory depression if taken in combination with PALEXIA. CNS depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect of tapentadol and impair vigilance. 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.

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).

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 (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.

Treatmentwith 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 ashypertensive crisis.

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.

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.

Lactation

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 affectcentral nervous systemfunctions(seesection 4.8). This has to be expected especially at the beginning of treatment, when any change of dosage occurs 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 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 table below lists adverse drug reactions that were identified from clinical trials performed with another immediate release formulation of tapentadol (PALEXIA film-coated tablets) and from post-marketing environment.. They are listed by class and frequency. Frequencies are defined as very common (³1/10); common (³1/100 to<1/10); uncommon (³1/1,000 to <1/100); rare (³1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

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ADVERSE DRUG REACTIONS

Symptoms

Human 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.

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 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 was similar to that observed with a strong opioid used as comparator.

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

Paediatric population

The 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).

The bioavailability as assessed byC_maxand AUC and all other pharmacokinetic parameters determined for tapentadol after administration of 100mg tapentadol as oral solutionwere similar compared to a100mg film-coated tablet (another oral immediate-release formulation). Therefore the information given below based on trials with film-coated tablets is also applicabletothe 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 175mg 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 trials, 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%.

Metabolism

In humans, the metabolism of tapentadol is extensive. About 97% of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% of the dose is excreted in urine as conjugated forms (55% glucuronide and 15%sulfate of tapentadol). Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3% of active substance is excreted in urine as unchanged active substance. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolised by conjugation. Therefore, active substance metabolism mediated by cytochrome P450 system is of less importance than 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 +/- 177ml/min. Terminal half-life is on average 4 hours after oral administration.

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 t1/2.The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Pharmacokinetic Interactions

Tapentadolis mainly metabolised by glucuronidation, andonly 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 (500mg twice daily for 2 days) and probenecid (500mg 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.

Tapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an invitro 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.

Sodium benzoate (E211)

Citric acid monohydrate

Sucralose (E955)

Raspberry flavor (containing propylene glycol)

Purified water

Not applicable

5years

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 an oral syringe and an adapter. The syringe is scaled in 0.25 milliliter increments with a minimum volume of 0.25ml and a maximum volume of 5ml.

100ml bottles

Grunenthal Ltd.

Regus Lakeside House,

1 Furzeground Way,

Stockley Park East,

Uxbridge,
Middlesex UB11 1BD,

United Kingdom

Date of first authorisation: 21st December 2010

Date of last renewal: 10th August 2015

September 2017